Curcuminoid compositions

ABSTRACT

The present invention relates to compositions comprising curcuminoids; in particular, compositions comprising curcuminoids that are highly water soluble. The present invention also relates to processes for providing such compositions and uses of such compositions.

FIELD OF THE INVENTION

The present invention relates to compositions comprising curcuminoids;in particular, compositions comprising curcuminoids that are highlywater soluble. The present invention also relates to processes forproviding such compositions and uses of such compositions.

BACKGROUND OF THE INVENTION

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

Turmeric and compounds isolated from turmeric, such as curcuminoidsincluding curcumin, have been used for a long time to treat a variety ofdiseases and conditions. Curcuminoids are natural yellow-orange pigmentsand hydrophobic polyphenols derived from the rhizome of the herb Curcumalonga. They are commonly isolated from the spice and food-coloring agentturmeric.

Turmeric extract contains approximately 75-80% curcumin, 15-20%demethoxycurcumin (DMC), and 0-10% bisdemethoxycurcumin (BDMC) (see FIG.1). Curcuminoids have a unique conjugated structure, abis-α,β-unsaturated β-diketone (commonly called diferuloylmethane),which exhibits keto-enol tautomerism having a predominant keto form inacidic and neutral solutions and stable enol form in alkaline medium(Hoehle S I, Pfeiffer E, Sólyom A M, Metzler M. Metabolism ofcurcuminoids in tissue slices and subcellular fractions from rat liver.J Agric Food Chem. 2006 Feb. 8; 54(3):756-64).

While the exact mechanism by which curcumin is able to impart valuablehealth benefits remains unclear, the overall positive effect is quitepronounced in some cases.

Curcumin is a highly pleiotropic molecule that was first shown toexhibit antibacterial activity in 1949. Since then, this polyphenol hasbeen shown to possess anti-inflammatory, hypoglycemic, antioxidant,wound-healing, and antimicrobial activities. Extensive preclinicalstudies and clinical trials over the past three decades have indicatedcurcumin's therapeutic potential against a wide range of human diseases(Gupta S C, Sung B, Kim J H, Prasad S, Li S, Aggarwal B B.Multitargeting by turmeric, the golden spice: From kitchen to clinic.Mol Nutr Food Res. 2013 September; 57(9):1510-28).

Although curcumin has shown efficacy against numerous human disorders,it is also known to have limited bioavailability due to poor absorption,rapid metabolism, and rapid systemic elimination.

Low serum levels, as well as limited tissue distribution and rapidmetabolism, have been reported when curcumin is orally administrated.For example, it has been demonstrated that even after oral doses of upto 12 g, blood serum levels of curcumin did not exceed the lowmicromolar level. In one clinical study with 4-8 g of curcumin, themaximum serum concentration observed was 1.3 μg/mL, while several otherclinical and animal studies reported serum levels in the lower nanogramper milliliter range (Anand P, Kunnumakkara A B, Newman R A, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007November-December; 4(6):807-18).

Curcumin has been found to be poorly soluble in water. For example, themaximum solubility of curcumin in aqueous buffer (pH 5.0) was reportedto be as low as 11 ng/ml (Tønnesen H H, Messon M, Loftsson T. Studies ofcurcumin and curcuminoids. XXVII. Cyclodextrin complexation: solubility,chemical and photochemical stability. Int J Pharm. 2002 Sep. 5;244(1-2):127-35).

Curcumin is relatively stable at acidic pH but rapidly decomposes at pHabove neutral and forms ferulic acid and feruloylmethane, the last onegiving then vanillin (FAO 2004. CURCUMIN Chemical and TechnicalAssessment (CTA) First draft prepared by Ivan Stankovic. Chemical andTechnical Assessment 61st JECFA).

Curcumin also exhibits very low intestinal absorption. The apparentpermeability coefficients of curcumin were found extremely low in an invitro human intestinal cell model (Papp value: 0.1×10-6 cm/s), whichcould predict, according to the correlation of Papp values determined inCaco-2 cells in vitro with human absorption in vivo, a low (0-20%)absorption in humans (Dempe J S, Scheerle R K, Pfeiffer E, Metzler M.Metabolism and permeability of curcumin in cultured Caco-2 cells. MolNutr Food Res. 2013 September; 57(9):1543-9).

Once absorbed, curcumin undergoes both phase I and phase II metabolism(see FIG. 2).

In phase I metabolism, curcumin and its two demethoxy congeners undergosuccessive reduction to their dihydro-, tetrahydro-, hexahydro-, andoctahydro-metabolites in the liver as well as in the intestinal mucosa.In phase II metabolism, both curcumin and its reductives metabolites areconjugated with glucuronic acid and sulfate and form phase IImetabolites.

Reduction and conjugation appear to be general metabolic pathways ofcurcuminoids, taking place in hepatic and intestinal tissues of rats andhumans. Thus, biological effects elicited by curcumin in tissues otherthan gastrointestinal tract are believed to be more likely due tocurcumin metabolites by several authors.

Curcumin has also been shown to be metabolized by intestinalmicroorganisms (see FIG. 3).

The microbial metabolism of curcumin was found to comprise a two-stepreduction, with curcumin being converted successively intodihydrocurcumin and then tetrahydrocurcumin by an NADPH-dependentcurcumin/dihydrocurcumin reductase (CurA) (Hassaninasab et al., 2011).

A recent study also reported that tetrahydroxycurcumin, but notcurcumin, could accumulate in tissue in rats, suggesting that microbiotacould be also considered as a potential actor in curcumin metabolism andbioavailability (Neyrinck A M, Alligier M, Memvanga P B, Névraumont E,Larondelle Y, Préat V, Cani P D, Delzenne N M. Curcuma longa extractassociated with white pepper lessens high fat diet-induced inflammationin subcutaneous adipose tissue. PLoS One. 2013 Nov. 19; 8(11):e81252).

The rapid metabolism, poor water solubility, instability at neutral pHand upon exposure to light and/or oxygen, and poor uptake by tissuesdrastically limits the potential utility of curcuminoids, including thepotential use of curcuminoids, such as curcumin in the treatment ofconditions such as cancer.

Several phase I and phase II clinical trials have demonstrated promisingeffects of oral curcumin administration in patients with colorectalneoplasia, advanced pancreatic and breast cancer—either with or withoutadditional chemotherapy. More specifically, curcumin displaysanti-melanoma efficiency both in vitro and in vivo.

Despite the great therapeutic potential of curcumin in a variety ofcancers (including melanoma), its clinical application has been stronglyhindered due to a number of limiting characteristics including: rapidmetabolism, poor water solubility, instability at neutral pH and uponexposure to light and/or oxygen, and poor uptake by tissues. The abovecharacteristics drastically limit the potential utility of curcumin inthe treatment of conditions such as cancer.

Due to poor water solubility and absorption characteristics, organicsolvents are typically used to dissolve curcuminoids, such as curcumin.For example, solvents such as dimethylsulfoxide (DMSO). However,although the use of such solvents helps to solubilize curcumin and toimprove availability, the use of organic solvents as a vehicle iscontroversial and undesirable, especially in an age where there isincreasing consumer demand for natural ingredients.

Another possibility to aid the water solubility of curcumin is viaemulsification. However, natural organic grade emulsifiers are rare andboth synthetic emulsifiers, such as polysorbate 80, and naturalemulsifiers, such as starch-based emulsifiers, are typically onlycapable of dispersing low levels (<7%) of curcumin in water.

Other strategies that have been explored in order to address the aboveshortcomings and to improve the therapeutic efficacy of curcumin includethe use of polymeric nanoparticles, polymer micelles and methodsincluding grafting curcumin to a hydrophilic polymer.

The present invention seeks to address the abovementioned problemsassociated with curcuminoid's poor solubility in water and provide acomposition comprising curcuminoids that is both highly soluble in waterand stable at physiological pH.

DISCLOSURE OF THE INVENTION

Composition

The present inventors have surprisingly found that a compositioncomprising at least about 20% curcuminoids by weight of the composition,gum arabic and an extract obtained from or obtainable from quillaja,wherein the composition comprises particles having an average diameterof from about 100 nm to about 10000 nm is highly water soluble andstable at physiological pH.

According to the present invention, there is provided a compositioncomprising:

(i) at least about 20% curcuminoids by weight of the composition;

(ii) gum arabic; and

(iii) an extract obtained or obtainable from quillaja,

wherein the composition comprises particles having an average diameterof from about 100 nm to about 10000 nm such as from about 100 nm toabout 700 nm or from about 1000 nm to about 6000 nm.

According to the present invention, there is also provided a compositioncomprising:

(iv) at least about 20% curcuminoids by weight of the composition;

(v) gum arabic; and

(vi) an extract obtained or obtainable from quillaja,

wherein the composition comprises particles having an average diameterof from about 100 nm to about 700 nm.

Such compositions may be referred to hereinafter as the “composition ofthe invention”.

The composition of the invention may be in the form of an emulsion orthe composition of the invention may be in the form a solid, forexample, in the form of a powder.

As used herein, the term “emulsion” refers to a type of colloid that isformed by combining two liquids that do not usually mix. Typically, oneof the liquids will contain a dispersion of the other liquid.

Sometimes the terms “colloid” and “emulsion” are used interchangeably,but as used herein the term emulsion applies when both phases of amixture are liquids. The particles in a colloid can be any phase ofmatter. So, an emulsion is a type of colloid, but not all colloids areemulsions.

A colloidal solution, occasionally identified as a colloidal suspension,is a mixture in which the substances are regularly suspended in a fluid.

Some compositions of the invention do not comprise fenugreek, forexample, some compositions of the invention do not comprise fenugreekfibre (i.e. fibre obtained or obtainable from fenugreek).

The composition of the invention may comprise small amounts of polyolsand/or low molecular weight sugars with preferably 1 or 2 monosaccharideunits, such as less than 5% by weight of the composition or less than2.5% by weight of the composition. Alternatively, the composition of theinvention may be free of polyols and/or low molecular weight sugars suchas those with 1 or 2 monosaccharide units, i.e. some compositions do notcontain any polyols and/or low molecular weight sugars, such as thosewith 1 or 2 monosaccharide units.

In the composition of the invention, the particles may have an averagediameter of from about 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm,800 nm, 900 nm, 1000 nm, 1100 nm, 1200 nm, 1300 nm, 1400 nm or 1500 nmto about 9000 nm, 8000 nm, 7000 nm, 6000 nm, 5000 nm, 4000 nm, 3000 nmor 2000 nm, such as from about 1000 nm to about 6000 nm. The particlesmay also have an average diameter of from about 200 nm to about 600 nm,or from about 300 nm to about 500 nm or about 400 nm.

For example, where the composition is in the form of an emulsion, thecomposition may, for example, comprise particles having an averagediameter of from about 550 nm to about 700 nm and particles having anaverage diameter of from about 100 nm to about 250 nm giving an averagediameter of about 400 nm.

Where the composition is in the form of a solid, such as a powder, thecomposition may, for example, comprise particles having an averagediameter of from about 1000 nm to about 6000 nm, such as from about 2000nm to about 4000 nm.

The particles in the composition of the invention may be in the form ofmicelles.

In the composition of the invention, for example where the compositionis in the form of a solid, the particles may be formed using suchtechniques known in the art, such as spray drying.

After the formation of the particles (for example, after drying, such asspray drying) the particles may be ground and/or milled (such as ballmilled) to provide a more uniform size.

The size and morphology of loaded curcumin micelle were analyzed bydynamic light scattering (DLS), and zeta potential (Z-potential), andscanning electron microscopy (SEM). For DLS and zeta-potential analysesa Zetasizer Nano ZS (NanoZS90, Malvern Instrument Ltd., UK) with a He/Nelaser (A=633 nm) at a fixed scattering angle of 90⁰ at temperature of(25±0.1° C.). For example, the size of the particles may be measured bymethod CQ-MO-304 as defined in the Examples below.

In the composition of the invention, the curcuminoids may be obtainedfrom any source. However, it is preferred that the curcuminoids areobtained from a natural source, i.e. the curcuminoids are not synthetic,but are plant based.

The composition of the invention may comprise at least about 25%curcuminoids or at least about 30% curcuminoids by weight of thecomposition.

For example, in the composition of the invention the curcuminoids may bepresent in an amount from about 20% to about 60%, such as from about 25%to about 50%, or from about 28% to about 48% by weight of thecomposition.

The curcuminoids may be provided by extraction and optionallypurification from the root (rhizome) of turmeric (Curcuma longa),oleoresin turmeric root, defatted oleoresin turmeric root and mixturesthereof, i.e. (i) the curcuminoids may be in the form of an extract orpurified extract of turmeric comprising from about 30% to about 100%curcuminoids, such as from about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,75%, 80%, 85% or 90% to about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%,55%, 50% or 45% curcuminoids based on the percentage of totalcurcuminoids in the extract.

Where the curcuminoids are provided as an extract of turmeric, theturmeric may be extracted using an alcohol-based extraction solvent,such as a water/alcohol mixture or an alcohol. For example, thealcohol-based extraction solvent may be water/methanol (i.e. a mixtureof water and methanol) or water/ethanol (i.e. a mixture of water andethanol) or methanol or ethanol.

Where the extraction solvent comprises a water/alcohol mixture the ratioof water to alcohol may be from about 25:75 to about 1:99, such as fromabout 20:80 to about 5:95 or about 10:90. For example, the extractionsolvent may be water/ethanol in a ratio of from about 25:75 to about1:99, such as from about 20:80 to about 5:95 or about 10:90.

The turmeric extract may then be further purified to provide an extractof curcuminoids comprising from about 30% to about 100% curcuminoids,such as from about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%or 90% to about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50% or 45%curcuminoids based on the percentage of total curcuminoids in theextract.

The purification of the extract may be performed using such techniquesknown in the art. Typically, the extract is purified using analcohol-based solvent, such as 100% methanol or 100% ethanol.

The turmeric extract may optionally be dried to remove any excesssolvent.

Where the curcuminoids are provided in the form of a turmeric extract aspreviously defined, the composition may comprise from about from about30% to about 50% turmeric extract, such as from about 35% to about 45%by weight of the composition. For example, the composition may comprisefrom about 35% (i.e. 35%) to about 45% turmeric extract by weight of thecomposition, where the turmeric extract comprises from about 85% toabout 95% curcuminoids by weight of the turmeric extract, providing acomposition that comprises from about 30% (i.e. 30%) to about 43%curcuminoids by weight of the composition.

The curcuminoids may be provided as a liquid or a powder, such as apowder. For example, a powdered turmeric extract.

As used herein, the term “curcuminoids” includes curcumin,demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC). For example,the turmeric extract may comprise from about 70% to about 85% curcumin(such as from about 75% to about 80%), from about 10% to about 25% DMC(such as from about 15% to about 20%) and from about 0% to about 10%BDMC.

The gum arabic in the composition of the invention may be present in anamount from about 40% to about 65% by weight of the composition, such asfrom about 50 to about 60% by weight of the composition or about 58% byweight of the composition.

The extract obtained or obtainable from quillaja in the composition ofthe invention may be present in an amount from about 0.1% to about 5% byweight of the composition, such as from about 0.5% to about 3% or about2% by weight of the composition.

As will be appreciated by the person skilled in the art, as used hereinthe term “obtainable from” means that the quillaja extract may beobtained from a plant of the Quillaja genus (such as Quillaja saponariamolina) or may be isolated from the plant of the Quillaja genus, or maybe obtained from an alternative source, for example by chemicalsynthesis or enzymatic production. Whereas the term “obtained” as usedherein, means that the extract is directly derived from the plant of theQuillaja genus.

The extract obtained or obtainable from quillaja in the composition ofthe invention may comprise at least 50% saponins, such as at least 60%saponins or at least 65% saponins by weight of the quillaja extract. Forexample, the quillaja used in the composition of the invention maycomprise from about 50% to about 80% or from about 60% to about 75%saponins by weight of the quillaja extract.

The extract obtained from or obtainable from quillaja used in theprocess of the invention may be in any form, such as a liquid or asolid. For example, the quillaja extract may be used in the form of asolid, such as a powder.

When present in the composition of the invention, the quillaja waterand/or other solvent, such as alcohol, may be added to the solid orliquid quillaja. For example, the quillaja may be present in thecomposition of the invention as an aqueous solution.

The composition of the invention may optionally comprise a plant and/orvegetable oil. For example, the composition of the invention maycomprise plant and/or vegetable oils selected from the group consistingof coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanutoil (ground nut oil), rapeseed oil, including canola oil, safflower oil,sesame oil, soybean oil, sunflower oil, and mixtures thereof.

The plant and/or vegetable oil present in the composition of theinvention may be present in an amount of from about 1% to about 20%plant and/or vegetable oil, such as from about 2.5% to about 10% orabout 5% by weight of the composition.

Unless otherwise stated herein, the weight percentages listed are basedon the total weight of (dry) composition obtained.

For the avoidance of doubt, preferences, options, particular featuresand the like indicated for a given aspect, feature or parameter of theinvention should, unless the context indicates otherwise, be regarded ashaving been disclosed in combination with any and all other preferences,options particular features and the like as indicated for the same orother aspects, features and parameters of the invention.

The term “about” as used herein, e.g. when referring to a measurablevalue (such as an amount or weight of a particular component in thereaction mixture), refers to variations of ±20%, ±10%, ±5%, ±1%, ±0.5%,or, particularly, ±0.1% relative to the specified amount. For example, avariation of ±0.5% with regards to the percentage of a component in thecomposition of the invention, means a variation of 0.5% relative to thepercentage given, i.e. ±0.5% of 10% would mean a variation from 9.5% to10.5%.

The composition of the invention may be provided in a solid or liquidform, preferably a solid form, such as a powder. By solid form, it isincluded that the compound may be provided as an amorphous solid, or asa crystalline or part-crystalline solid.

The composition of the invention is typically highly water solubleand/or stable at a pH of 4 or more, such as a pH from about 4 to about7.

By the term water soluble we mean that at least about 50%, such as atleast about 60%, 70%, 80%, 90% or 95% of the composition will dissolvein water at room temperature, i.e. a temperature of about 25° C.

Compositions and Administration

According to the present invention, the composition of the invention maybe provided in the form of a nutraceutical formulation, a dietary orfood product for humans or animals (such as functional foodformulations, i.e. food, drink, feed or pet food or a food, drink, feedor pet food supplements), a herbicide, a nutritional supplement, afragrance or flavouring, a pharmaceutical or veterinary formulation, anoenological or cosmetic formulation or may form a part of anutraceutical formulation, a dietary or food product for humans oranimals (such as functional food formulations, i.e. food, drink, feed orpet food or a food, drink, feed or pet food supplements), a nutritionalsupplement, a fragrance or flavouring, a pharmaceutical or veterinaryformulation, an oenological or cosmetic formulation.

For example, the present invention provides a nutraceutical formulation,a dietary or food product for humans or animals (such as functional foodformulations, i.e. food, drink, feed or pet food or a food, drink, feedor pet food supplements), a nutritional supplement, a fragrance orflavouring, a pharmaceutical or veterinary formulation, an oenologicalor cosmetic formulation consisting of, consisting essentially of (i.e.at least 90% w/w of the nutraceutical formulation, a dietary or foodproduct for humans or animals (such as functional food formulations,i.e. food, drink, feed or pet food or a food, drink, feed or pet foodsupplements), a nutritional supplement, a fragrance or flavouring, apharmaceutical or veterinary formulation, an oenological or cosmeticformulation is the composition of the invention, such as at least 95%,or 99% or 99.5%) or comprising the composition of the invention.

The present invention also provides the use of a composition of theinvention in a nutraceutical formulation, a dietary or food product forhumans or animals (such as functional food formulations, i.e. food,drink, feed or pet food or a food, drink, feed or pet food supplements),a nutritional supplement, a fragrance or flavouring, a pharmaceutical orveterinary formulation, an oenological or cosmetic formulation.

Where the composition of the invention is in the form of a nutraceuticalformulation, a dietary or food product for humans or animals (such asfunctional food formulations, i.e. food, drink, feed or pet food or afood, drink, feed or pet food supplements), a herbicide, a nutritionalsupplement, a fragrance or flavouring, a pharmaceutical or veterinaryformulation, an oenological or cosmetic formulation or may form a partof a nutraceutical formulation, a dietary or food product for humans oranimals (such as functional food formulations, i.e. food, drink, feed orpet food or a food, drink, feed or pet food supplements), a nutritionalsupplement, a fragrance or flavouring, a pharmaceutical or veterinaryformulation, an oenological or cosmetic formulation, may optionallyfurther comprise a pharmaceutically/veterinary ingredients, such asexcipients or carriers or (function) food acceptable ingredients andmixtures thereof as appropriate.

For the avoidance of doubt, in this specification when we use the term“comprising” or “comprises” we mean that the extract or compositionbeing described must contain the listed ingredient(s) but may optionallycontain additional ingredients. When we use the term “consistingessentially of” or “consists essentially of” we mean that the extract orcomposition being described must contain the listed ingredient(s) andmay also contain small (for example up to 5% by weight, or up to 1% or0.1% by weight) of other ingredients provided that any additionalingredients do not affect the essential properties of the extract orcomposition. When we use the term “consisting of” or “consists of” wemean that the extract or composition being described must contain thelisted ingredient(s) only.

It is also intended that the terms “comprise” or “comprises” or“comprising” may be replaced with “consist” or “consisting” or“consisting essentially of” throughout the application as required.

As used herein, references to pharmaceutically acceptable excipients mayrefer to pharmaceutically acceptable adjuvants, diluents and/or carriersas known to those skilled in the art.

Food acceptable ingredients include those known in the art (includingthose also referred to herein as pharmaceutically acceptable excipients)and that can be natural or non-natural, i.e. their structure may occurin nature or not. In certain instances, they can originate from naturalcompounds and be later modified (e.g. maltodextrin).

By “pharmaceutically/nutraceutically acceptable” we mean that theadditional components of the composition are sterile and pyrogen free.Such components must also be “acceptable” in the sense of beingcompatible with the composition of the invention and not deleterious tothe recipients thereof. Thus, “pharmaceutically acceptable” includes anycompound(s) used in forming a part of the formulation that is intendedto act merely as an excipient, i.e. not intended to have biologicalactivity itself. Thus, the pharmaceutically acceptable excipient isgenerally safe, non-toxic, and neither biologically nor otherwiseundesirable.

Where the composition of the invention forms part of a nutraceuticalformulation, a dietary or food product for humans or animals (such asfunctional food formulations, i.e. food, drink, feed or pet food or afood, drink, feed or pet food supplements), a nutritional supplement, afragrance or flavouring, a pharmaceutical or veterinary formulation, anoenological or cosmetic formulation, the composition of the invention ispresent in the nutraceutical formulation, a dietary or food product forhumans or animals (such as functional food formulations, i.e. food,drink, feed or pet food or a food, drink, feed or pet food supplements),a nutritional supplement, a fragrance or flavouring, a pharmaceutical orveterinary formulation, an oenological or cosmetic formulation in anamount from about 1 to about 99% by weight of the nutraceuticalformulation, a dietary or food product for humans or animals (such asfunctional food formulations, i.e. food, drink, feed or pet food or afood, drink, feed or pet food supplements), a nutritional supplement, afragrance or flavouring, a pharmaceutical or veterinary formulation, anoenological or cosmetic formulation, such as from about 10%, 20%, 30%,40%, 50%, 60%, 70%, 80% or 90% to about 90%, 80%, 70%, 60%, 50%, 40%,30%, or 20% by weight of the nutraceutical formulation, a dietary orfood product for humans or animals (such as functional foodformulations, i.e. food, drink, feed or pet food or a food, drink, feedor pet food supplements), a nutritional supplement, a fragrance orflavouring, a pharmaceutical or veterinary formulation, an oenologicalor cosmetic formulation.

Administration

The skilled person will understand that the composition of theinvention, either where the composition is in the form of nutraceuticalformulation, a dietary or food product for humans or animals (such asfunctional food formulations, i.e. food, drink, feed or pet food or afood, drink, feed or pet food supplements), a nutritional supplement, afragrance or flavouring, a pharmaceutical or veterinary formulation, anoenological or cosmetic formulation or where the nutraceuticalformulation, a dietary or food product for humans or animals (such asfunctional food formulations, i.e. food, drink, feed or pet food or afood, drink, feed or pet food supplements), a nutritional supplement, afragrance or flavouring, a pharmaceutical or veterinary formulation, anoenological or cosmetic formulation comprises the composition of theinvention, the nutraceutical formulation, a dietary or food product forhumans or animals (such as functional food formulations, i.e. food,drink, feed or pet food or a food, drink, feed or pet food supplements),a nutritional supplement, a fragrance or flavouring, a pharmaceutical orveterinary formulation, an oenological or cosmetic formulation may beadministered to a patient or subject (e.g. a human or animal patient orsubject) by any suitable route, such as by the oral, rectal, nasal,pulmonary, buccal, sublingual, transdermal, intracisternal,intraperitoneal, and parenteral (including subcutaneous, intramuscular,intrathecal, intravenous and intradermal) route.

In particular, compositions of the invention and nutraceuticalformulations, a dietary or food product for humans or animals (such asfunctional food formulations, i.e. food, drink, feed or pet food or afood, drink, feed or pet food supplements), a nutritional supplement, afragrance or flavouring, a pharmaceutical or veterinary formulation, anoenological or cosmetic formulation comprising the composition of theinvention may be administered orally. In such instances, pharmaceuticalcompositions according to the present invention may be specificallyformulated for administration by the oral route.

Pharmaceutical formulations for oral administration include solid dosageforms such as hard or soft capsules, tablets, troches, dragees, pills,lozenges, powders and granules. Where appropriate, they can be preparedwith coatings such as enteric coatings, or they can be formulated so asto provide controlled release of the active ingredient, such assustained or prolonged release, according to methods well known in theart.

Liquid dosage forms for oral administration include solutions,emulsions, aqueous or oily/oil based suspensions, syrups and elixirs.

Nutraceutical formulations, a dietary or food product for humans oranimals (such as functional food formulations, i.e. food, drink, feed orpet food or a food, drink, feed or pet food supplements), a nutritionalsupplement, a fragrance or flavouring, a pharmaceutical or veterinaryformulation, an oenological or cosmetic formulation described herein,such as those intended for oral administration, may be preparedaccording to methods known to those skilled in the art, such as bybringing the components of the composition into admixture.

Such nutraceutical formulation, a dietary or food product for humans oranimals (such as functional food formulations, i.e. food, drink, feed orpet food or a food, drink, feed or pet food supplements), a nutritionalsupplement, a fragrance or flavouring, a pharmaceutical or veterinaryformulation, an oenological or cosmetic formulations as described hereinmay contain one or more additional components selected from the groupconsisting of food ingredients, such as sweetening agents, flavouringagents, colouring agents and preserving agents. Tablets may contain theactive ingredient(s) in admixture with non-toxic pharmaceuticallyacceptable excipients (or ingredients) which are suitable for themanufacture of tablets. These excipients (or ingredients) may, forexample, be: inert diluents, such as calcium carbonate, sodiumcarbonate, lactose, calcium phosphate or sodium phosphate; granulatingand disintegrating agents, for example, corn starch, maltodextrin oralginic acid; binding agents, for example, starch, gelatine or acacia;and lubricating agents, for example magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solutions and various organic solvents.Examples of solid carriers are lactose, terra alba, sucrose,cyclodextrin, maltodextrin, talc, gelatine, agar, pectin, acacia,magnesium stearate, stearic acid, arabic gum, modified starch and loweralkyl ethers of cellulose. Examples of liquid carriers are syrup, peanutoil, olive oil, phospholipids, fatty acids, fatty acid amines,polyoxyethylene and water. Moreover, the carrier or diluent may includeany sustained release material known in the art, such as glycerylmonostearate or glyceryl distearate, alone or mixed with a wax.

Depending on the disorder, and the patient, to be treated, as well asthe route of administration, compositions of the invention may beadministered at varying doses (i.e. therapeutically effective doses, asadministered to a patient in need thereof). In this regard, the skilledperson will appreciate that the dose administered to a mammal,particularly a human, in the context of the present invention should besufficient to effect a therapeutic response in the mammal over areasonable timeframe. One skilled in the art will recognize that theselection of the exact dose and formulation and the most appropriatedelivery regimen will also be influenced by inter alia thepharmacological properties of the formulation, the nature and severityof the condition being treated, and the physical condition and mentalacuity of the recipient, as well as the potency of the specificcompound, the age, condition, body weight, sex and response of thepatient to be treated, and the stage/severity of the disease.

Typically, the composition of the invention or the nutraceuticalformulation, a dietary or food product for humans or animals (such asfunctional food formulations, i.e. food, drink, feed or pet food or afood, drink, feed or pet food supplements), a nutritional supplement, afragrance or flavouring, a pharmaceutical or veterinary formulation, anoenological or cosmetic formulation is administered to providecurcuminoids in an amount of from about 100 mg/day to about 2000 mg/day,or from about 500 mg/day to about 1500 mg/day, or about 1000 mg/day,such as from about 300 mg/day to about 1000 mg/day. For example, thecomposition or the nutraceutical formulation, a dietary or food productfor humans or animals (such as functional food formulations, i.e. food,drink, feed or pet food or a food, drink, feed or pet food supplements),a nutritional supplement, a fragrance or flavouring, a pharmaceutical orveterinary formulation, an oenological or cosmetic formulation mayprovide curcuminoids in an amount of from about 1 to about 10 mg/kg ofbody weight, such as from about 2.5 to about 7.5 mg/kg of body weight orabout 5 mg/kg.

In any event, the medical practitioner, or other skilled person, will beable to determine routinely the actual dosage, which will be mostsuitable for an individual patient. The above-mentioned dosages areexemplary of the average case; there can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

Process for the Preparation of Compositions of the Invention

The present invention provides a process for the preparation of acomposition of the invention as previously defined, wherein the processcomprises the steps of:

(i) preparing an aqueous solution of curcuminoids;

(ii) mixing the aqueous solution from (i) with an aqueous gum arabicsolution, and extract obtained or obtainable from quillaja, andoptionally the plant and/or vegetable oil, to provide an emulsion; andoptionally

(iii) drying the product of (ii) to provide a composition comprisingparticles having an average diameter of from about 100 nm to about 10000nm, such as from about 100 nm to about 700 nm or from about 1000 nm toabout 6000 nm.

For example, the present invention provides a process for thepreparation of a composition of the invention as previously defined,wherein the process comprises the steps of:

(i) preparing an aqueous solution of curcuminoids;

(ii) mixing the aqueous solution from (i) with an aqueous gum arabicsolution, and extract obtained or obtainable from quillaja, andoptionally the plant and/or vegetable oil, to provide an emulsion; and

(iii) drying the product of (ii) to provide a composition comprisingparticles having an average diameter of from about 100 nm to about 10000nm such as from about 100 nm to about 700 nm or from about 1000 nm toabout 6000 nm.

Such processes are hereinafter referred to as the process of theinvention.

In the process of the invention, the aqueous solution of gum arabic maybe mixed with the aqueous solution of curcuminoids before mixing withthe extract obtained or obtainable from quillaja and optionally theplant and/or vegetable oil, i.e. the process of the invention maycomprise:

(i) preparing an aqueous solution of curcuminoids;

(ii) mixing the aqueous solution from (i) with an aqueous gum arabicsolution;

(iii) mixing the extract obtained or obtainable from quillaja andoptionally the plant and/or vegetable oil to the product of (ii) toprovide an emulsion; and optionally

(iv) drying the product of (iii) (such as by spray drying) to provide acomposition comprising particles having an average diameter of fromabout 100 nm to about 10000 nm, such as from about 100 nm to about 700nm or from about 1000 nm to about 6000 nm.

After drying, (such as spray drying) the particles may be ground and/ormilled (such as ball milled) to provide a more uniform size.

In the process of the invention, the particles may have an averagediameter from about 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800nm, 900 nm, 1000 nm, 1100 nm, 1200 nm, 1300 nm, 1400 nm or 1500 nm toabout 9000 nm, 8000 nm, 7000 nm, 6000 nm, 5000 nm, 4000 nm, 3000 nm or2000 nm, such as from about 1000 nm to about 6000 nm. The particles mayalso have an average diameter of from about 200 nm to about 600 nm, orfrom about 300 nm to about 500 nm or about 400 nm.

For example, where the composition of the invention is in the form of anemulsion (i.e. before the drying step), the composition may compriseparticles having an average diameter of from about 550 nm to about 700nm and particles having an average diameter of from about 100 nm toabout 250 nm giving an average diameter of about 400 nm.

Where the composition is in the form of a solid, such as a powder (i.e.after the drying step), the composition may comprise particles having anaverage diameter of from about 1000 nm to about 6000 nm, such as fromabout 2000 nm to about 4000 nm.

The particles in the composition may be in the form of micelles.

In the process of the invention, the curcuminoids present in the aqueoussolution of curcuminoids may be from any source as previously definedwith respect to the composition of the invention.

Typically, in the process of the invention, the curcuminoids may have apurity (based on total curcuminoids) of from about 5% to about 100% byweight of the curcuminoids source, i.e. the turmeric or curcuminoidextract may comprise from about 30% to about 100% curcuminoids, such asfrom about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 3080%, 85% or90% to about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50% or 45%curcuminoids based on the percentage of total curcuminoids in theextract.

In the process of the invention, the curcuminoids may be mixed withwater in a weight ratio of from about 2:1 (curcuminoids:water) to about4:1, such as about 3:1, to provide the aqueous solution of curcuminoids.

Typically, in the process of the invention, the weight concentration ofcurcuminoids in the aqueous solution may be from about 1% to about 95%,such as from about 5% to about 80% or from about 7% to about 40%.

In the process of the invention, the aqueous gum arabic solution may beprepared by mixing gum arabic with water in a ratio of gum arabic:waterof from about 2:1 to about 4:1, such as about 3:1.

The aqueous gum arabic solution may have a weight concentration of gumarabic of from about 30% to about 70%, such as from about 40% to about60%.

Typically, the aqueous curcuminoids solution and aqueous gum arabicsolution are mixed using agitation.

In the process of the invention, the plant and/or vegetable oil, may befrom any plant and/or vegetable source. For example, the plant and/orvegetable oil may be sunflower oil.

Typically, in the process of the invention, the plant and/or vegetableoil may be present in an amount of from about 1% to about 10% plantand/or vegetable oil, such as from about 2.5% to about 7.5% or about 5%.

In the process of the invention, the extract obtained from or obtainablefrom quillaja may be as defined previously with respect to thecomposition of the invention.

The extract obtained from or obtainable from quillaja used in theprocess of the invention may be in any form, such as a liquid or asolid. For example, the quillaja extract may be used in the form of asolid, such as a powder.

Typically, in the process of the invention, the quillaja may be presentin an amount of from 30 about 0.5% to about 5% quillaja, such as fromabout 1% to about 3%, or about 2%.

In the process of the invention, the plant and/or vegetable oil andquillaja extract may be mixed using agitation.

Mixing the aqueous solution of curcuminoids, aqueous gum arabicsolution, plant and/or vegetable oil and quillaja as defined aboveprovide an emulsion.

The resulting emulsion may be dried using such techniques as known inthe art to provide a composition comprises particles (such as micelles)having an average diameter of from about 200 nm, 300 nm, 400 nm, 500 nm,600 nm, 700 nm, 800 nm, 900 nm, 1000 nm, 1100 nm, 1200 nm, 1300 nm, 1400nm or 1500 nm to about 9000 nm, 8000 nm, 7000 nm, 6000 nm, 5000 nm, 4000nm, 3000 nm or 2000 nm, such as from about 1000 nm to about 6000 nm. Theparticles may also have an average diameter of from about 100 nm toabout 700 nm, or from about 200 nm to about 600 nm, such as from about300 nm to about 500 nm, or about 400 nm. Typically, the emulsion isspray dried.

The process of the invention may optionally include a step of removingadditional solvent as required in order to provide a substantially dryproduct, i.e. a product where at least 90%, such as at least 95% or 99%of the water present has been removed.

Methods and Uses

The high water solubility and stability of the composition of theinvention means that the composition of the invention can be used toimprove bioaccessibility, bioavailability bioefficacy and/or bioactivityof curcuminoids in mammals.

The improved bioaccessibility, bioavailability, bioefficacy and/orbioactivity of curcuminoids allows for the composition of the inventionto be used to prevent and/or treat diseases where in the past the pooraqueous solubility and stability of curcuminoids has been an issue.

Thus, the present invention provides a method for improvingbioaccessibility, bioavailability bioefficacy and/or bioactivity ofcurcuminoids in mammals comprising the administration of saidcurcuminoids in the form of a composition of the invention as previouslydefined.

The method maybe referred to hereinafter as the “method of theinvention”.

The present invention also provides the use of a composition of theinvention as previously defined for improving the bioaccessibility,bioavailability bioefficacy and/or bioactivity of curcuminoids inmammals.

The use maybe referred to hereinafter as the “use of the invention”.

In the method or uses described herein the improvement inbioaccessibility, bioavailability bioefficacy and/or bioactivity ofcurcuminoids in mammals may be due to the composition providing improvedgastrointestinal resistance of the curcuminoids and/or improvedabsorption of curcuminoids by intestinal cells and/or improved bloodcirculation.

In the methods or uses described herein the improvement inbioaccessibility, bioavailability bioefficacy and/or bioactivity ofcurcuminoids in mammals may be due to the composition providing improvedwater solubility and/or improved stability at a pH from about 4 to about7.

Thus, the present invention provides a method for improving the watersolubility and/or pH stability of curcuminoids, wherein the methodcomprises the administration of said curcuminoids in the form of acomposition of the invention as previously defined.

The present invention also provides the use of a composition aspreviously defined for improving the water solubility and/or pHstability of curcuminoids.

In the methods or uses described herein, the curcuminoids may beselected from the group consisting of curcumin and its phase I or phaseII metabolites, demethoxycurcumin and its phase I or phase IImetabolites, bisdemethoxycurcumin and its phase I or phase IImetabolites and mixtures thereof. For example, the phase I and/or phaseII metabolites may be selected from the group consisting of curcuminglucuronide, curcumin sulfate, DMC glucuronide, DMC sulfate, BDMCglucuronide, BDMC sulfate, tetrahydrocurcumin (THC), THC glucuronide,THC sulfate, hexahydrocurcumin (HHC), HHC glucuronide, HHC sulfate andmixtures thereof.

In the compositions, methods or uses described herein, the curcuminoidsmay be in their unmetabolized form, for example the forms or curcumin,DMC and BDMC that have not undergone glucuronide or sulfate addition.

In the methods and uses described herein, the mammal may be a human.

As used herein, the term “bioavailability” can be defined as thefraction of ingested component available at the site of action forutilization in normal physiological functions and is determined throughin vivo assays (Guerra A, Etienne-Mesmin L, Livrelli V et al (2012)Relevance and challenges in modeling human gastric and small intestinaldigestion. Trends Biotechnol 30:591-600). Bioavailability is the resultof three main steps: digestibility and solubility of the element in thegastrointestinal tract; absorption of the element by the intestinalcells and transport into the circulation; and incorporation from thecirculation to the functional entity or target (Wienk K J H, Marx J J M,Beynen A C (1999) The concept of iron bioavailability and itsassessment. Eur J Nutr 38:51-75; Etcheverry P, Grusak M A, Fleige L E(2012) Application of in vitro bioaccessibility and bioavailabilitymethods for calcium, carotenoids, folate, iron, magnesium, polyphenols,zinc, and vitamins B6, B12, D, and E. Front Physiol 3:1-21).

As used herein, the term “bioaccessibility” can be defined as thefraction of a compound that is released from its food matrix within thegastrointestinal tract and thus becomes available for intestinalabsorption (typically established from in vitro procedures). It includesthe sequence of events that take place during food digestion fortransformation into potentially bioaccessible material but excludesabsorption/assimilation through epithelial tissue and pre-systemicmetabolism (both intestinal and hepatic). (Alegria A., Garcia-Llatas G.,Cilla A. (2015) Static Digestion Models: General Introduction. In:Verhoeckx K. et al. (eds) The Impact of Food Bioactives on Health.Springer, Cham)

As used herein, the term “bioactivity” can be defined as how thenutrient or bioactive compound is transported and reaches the targettissue, how it interacts with biomolecules, the metabolism orbiotransformation it may experience, and the generation of biomarkersand the physiological responses induced (Alegria A., Garcia-Llatas G.,Cilla A. (2015) Static Digestion Models: General Introduction. In:Verhoeckx K. et al. (eds) The Impact of Food Bioactives on Health.Springer, Cham).

BRIEF DESCRIPTION OF FIGURES

FIG. 1—Chemical structures of the curcuminoids from turmeric.

FIG. 2—Phase I and phase II metabolites of curcumin

FIG. 3—Bacterial metabolites of curcumin

FIG. 4—the effect of pH on the composition of the invention colourdissolved in demineralized water (0.4%).

FIG. 5—the DLS profile of loaded of composition of the invention.

FIG. 6—The Z-potential of the composition of the invention andindividual components of the composition in different pHs.

FIG. 7—Scanning electron microscopy (SEM) image of the composition ofthe invention at ×300.

FIG. 8—Scanning electron microscopy (SEM) image of the composition ofthe invention at ×1300.

FIG. 9—Scanning electron microscopy (SEM) image of the composition ofthe invention at ×9200.

FIG. 10—LDH activity measured on the apical supernatant collected fromthe Caco-2 cells treated with samples coming from the differentgastrointestinal tract compartments after 4 h of incubation, data fromthe standard curcumin extract. Bars depict Mean±SEM. PP: pure product;SI: small intestine; ST: stomach; TB: transport buffer. (*), (**) and(***) correspond to significances at p<0.05, p<0.01 and p<0.001,respectively, compared to TB+colon 48 h.

FIG. 11—LDH activity measured on the apical supernatant collected fromthe Caco-2 cells treated with samples coming from the differentgastrointestinal tract compartments after 4 h of incubation, data fromthe standard curcumin extract with data normalized to the TB+colon 48 hsample (100%). Bars depict Mean±SEM. PP: pure product; SI: smallintestine; ST: stomach; TB: transport buffer. (*), (**) and (***)correspond to significances at p<0.05, p<0.01 and p<0.001, respectively,compared to TB+colon 48 h.

FIG. 12—LDH activity measured on the apical supernatant collected fromthe Caco-2 cells treated with samples coming from the differentgastrointestinal tract compartments after 4 h of incubation, data fromthe turmeric phytosome formulation. Bars depict Mean±SEM. PP: pureproduct; SI: small intestine; ST: stomach; TB: transport buffer. (*),(**) and (***) correspond to significances at p<0.05, p<0.01 andp<0.001, respectively, compared to TB+colon 48 h.

FIG. 13—LDH activity measured on the apical supernatant collected fromthe Caco-2 cells treated with samples coming from the differentgastrointestinal tract compartments after 4 h of incubation, data fromthe turmeric phytosome formulation with data normalized to the TB+colon48 h sample (100%). Bars depict Mean±SEM. PP: pure product; SI: smallintestine; ST: stomach; TB: transport buffer. (*), (**) and (***)correspond to significances at p<0.05, p<0.01 and p<0.001, respectively,compared to TB+colon 48 h.

FIG. 14—LDH activity measured on the apical supernatant collected fromthe Caco-2 cells treated with samples coming from the differentgastrointestinal tract compartments after 4 h of incubation, data fromthe quillaja based formulation. Bars depict Mean±SEM. PP: pure product;SI: small intestine; ST: stomach; TB: transport buffer. (*), (**) and(***) correspond to significances at p<0.05, p<0.01 and p<0.001,respectively, compared to TB+colon 48 h.

FIG. 15—LDH activity measured on the apical supernatant collected fromthe Caco-2 cells treated with samples coming from the differentgastrointestinal tract compartments after 4 h of incubation, data fromthe quillaja based formulation with data normalized to the TB+colon 48 hsample (100%). Bars depict Mean±SEM. PP: pure product; SI: smallintestine; ST: stomach; TB: transport buffer. (*), (**) and (***)correspond to significances at p<0.05, p<0.01 and p<0.001, respectively,compared to TB+colon 48 h.

FIG. 16—Evolution of the food intake over the acclimatization andhabituation periods of groups of mice sacrificed at the same time point.Mean daily food intake (g) of the different experimental groups duringthe acclimatization (J0-J7) and habituation (J8-J14) periods.

FIG. 17—Evolution of body weight over the acclimatization andhabituation periods of groups of mice sacrificed at the same time point.Mean body weight (g) of the different experimental groups during thesame periods. Data are represented as mean±SEM.

FIG. 18—Time-course of total curcuminoids levels (sum of curcumin, DMC,BDMC and their relative metabolites curcumin glucuronide and sulfate,DMC glucuronide and sulfate, BDMC glucuronide and sulfate, THC, THCglucuronide and sulfate, HHC, HHC glucuronide and sulfate) in mouseplasma after a single oral dose of Turmeric Phytosome formulation versusstandard turmeric extract containing 300 mg/kg of curcuminoids. *, **,***: The Turmeric Phytosome formulation significantly different(post-hoc t-test) at each time point from standard turmeric extract(p<0.05, p<0.01, p<0.001 respectively).

FIG. 19—Time-course of total curcuminoids levels (sum of curcumin, DMC,BDMC and their relative metabolites curcumin glucuronide and sulfate,DMC glucuronide and sulfate, BDMC glucuronide and sulfate, THC, THCglucuronide and sulfate, HHC, HHC glucuronide and sulfate) in mouseplasma after a single oral dose of the composition as used in themethods/uses of the invention versus standard turmeric extractcontaining 300 mg/kg of curcuminoids. *, **, ***: The composition asused in the methods/uses of the invention significantly different(post-hoc t-test) at each time point from standard turmeric extract(p<0.05, p<0.01, p<0.001 respectively).

FIG. 20: Total curcuminoids and metabolites (sum of curcumin, DMC, BDMCand their relative metabolites curcumin glucuronide and sulfate, DMCglucuronide and sulfate, BDMC glucuronide and sulfate, THC, THCglucuronide and sulfate, HHC, HHC glucuronide and sulfate) concentration(ppm) as a function of time (h) after consumption of the differentformulations (n=72 per formulation). ^(□), ^(□□): Turmeric Phytosomesignificantly different from standard turmeric extract (p<0.05, p<0.01respectively); *, **, ***: The composition as used in the methods/usesof the invention significantly different from standard turmeric extract(p<0.05, p<0.01, p<0.001 respectively).

FIG. 21—Corresponding area under the curve AUC(0-8 h) of the differentformulations.

FIG. 22—Corresponding area under the curve AUC(0-∞) of the differentformulations.

FIG. 23—Cmax (concentration at Tmax) of the different formulations.

FIG. 24—Graphical representation of Dose-normalized of AUC_(0-24h) forthe ITT population.

FIG. 25—Graphical representation of Dose-normalized of AUC_(0-8h) forthe ITT population.

FIG. 26—Graphical representation of Dose-normalized of AUC_(0-∞) for theITT population.

FIG. 27—Graphical representation of AUC₀₋₂₄ h for the ITT population.

FIG. 28—Graphical representation of AUC_(0-8h) for the ITT population.

FIG. 29—Graphical representation of AUC_(0-∞) for the ITT population.

FIG. 30—Graphical representation of the normalised Cmax for the ITTpopulation.

FIG. 31—Graphical representation of the Cmax for the ITT population.

FIG. 32—Graphical representation of the relative bioavailability between0 and 24 hours for the ITT population.

FIG. 33—Graphical representation of the relative bioavailability between0 and 8 hours for the ITT population.

FIG. 34—Graphical representation of the relative bioavailability between0 and infinity for the ITT population.

FIG. 35—Graphical representation of the half-life for the ITTpopulation.

FIG. 36—Graphical representation of terminal elimination rate constantfor the ITT population.

FIG. 37—Graphical representation of the Tmax for the ITT population.

EXAMPLES

The present invention will be further described by reference to thefollowing, non-limiting examples.

Example 1—Preparation of Alkaline Organic Curcumin Solution

A mixture of curcuminoids in water was prepared using an organicpurified curcuminoid extract (at least at 10% but preferably at 95% ofpurity (total curcuminoids)) in distilled water (3 volumes powderweight/water).

Example 2—Preparation of a Composition of the Invention

A 58% gum Arabic mixture (substrate) was prepared using distilled water(3 volumes powder weight/water). 500 ml of the aqueous gum arabicsolution was added 500 ml of the curcuminoid solution prepared inExample 1 under agitation (5000 rpm) and to this was added 5% of organicsunflower oil and 2% of organic quillaja standardized in saponins.

The resulting mixture was agitated at 5000 rpm for ten minutes. Theresulting emulsion was then spray dried.

Example 3—Characterization of a Composition of the Invention The sizeand morphology of the composition of the invention was analyzed bydynamic light scattering (DLS), and zeta potential (Z-potential), andscanning electron microscopy (SEM). For DLS and zeta-potential analysesa Zetasizer Nano ZS (NanoZS90, Malvern Instrument Ltd., UK) with a He/Nelaser (λ=633 nm) at a fixed scattering angle of 90° at temperature of(25±0.1° C.) was used.

The samples used were in liquid emulsion form (last step before drying).The samples were suspended in demineralized water at a volumeconcentration of 0.4% and 1 minute of ultrasound was applied. DLSanalysis was immediately performed at these samples (measure time=60seconds). The analysis of zeta-potential was performed in a large pHrange (from 2 to 11).

The samples were prepared and analyzed at different pHs as follows bythe use of 0.1M HCl and 0.1M NaOH solutions. The 10 samples (pH=2, 3, 4,5, 6, 7, 8, 9, 10 and 11) obtained were stored at room temperature (23°C.) (FIG. 4).

As shown in FIG. 4, the colour of the composition of the invention inwater is driven by pH. The keto form (yellow) is the predominant formpresent in solution when pH range vary from acid to neutral (from 2- to7). At pH 8 and 9 colour solution turns to orange, and at pH 10 and 11 atranslucid reddish colour is predominant. The colour change is due tosequential deprotonation of hydroxyl-groups of curcumin molecule drivenby pH increasing which gives a higher solubility and instability tocurcumin.

The DLS analysis results are showed in FIG. 5. There are two groups ofparticle size individuals. One centralized at 616±160 nm (20.8% of totalindividuals) and the most interesting one centralized at 188±42 nm(79.2% of the total individuals).

The mean hydrodynamic particle size of loaded curcumin in water solution(pH 5.4) was found to be 476.5 nm with a PDI (polydispersity index) of0.337.

FIG. 6 shows the Z-potential of the composition of the invention atdifferent pHs (from 2 to 11). The higher Z-potential, the more unstablemixture is. The composition of the invention has a negative Z-potentialbetween pH 2 and pH 11. The particles are negatively charged in theaqueous phase. At pH 2 the Z-potential is close to 0 (isoelectric point:pH for which the potential is zero), where we have an instability zoneof the emulsions.

Between pH 2 and pH 4, the Z-potential is relatively low (<25 mV) and atpH greater than or equal to 4, the sample enters a zone of stability.This stability is strongly confirmed from pH 5. A rapid shift in theisoelectric point was observed in pH 8.0 the zeta-potential of theloaded curcumin was surprisingly higher in pH range from 2 to 7. In theaqueous phase at pHs<4.0, loaded curcumin are usually at their lowestsurface energy state. At pH 8.0, the loaded curcumin is likely to orientits low electronic charge side towards Arabic gum and expose its highelectronic charge side to interact with water, which leads to anelevated zeta-potential.

FIG. 6 clearly shows that the claimed composition is stable whendispersed in an aqueous solution at pH greater than 4.

Example 4—Particle Size Distribution (PSD) of a Composition of theInvention Using CQ-MO-304

Materials and Reagents

Material—Mastersizer 3000 from Malvern Instrument, or equivalent;

-   -   Hydro 2000SM sample dispersion unit, or equivalent (for liquid        phase),    -   Malvern AERO S sample dispersion unit, or equivalent (for solid        phases).

Reagent—Water

Procedure

-   -   Analytical parameters        -   background time: 10 seconds        -   Measurement time@10 seconds        -   Refractive index of distilled water: 1.33        -   Result calculation: general purpose        -   Pump/stir speed: 1800 RPM        -   liquid dispersant: water        -   solid dispersant: ambient air    -   Specific parameters        -   100705 (refractive index: 1, adsorption: 1)        -   100019 (refractive index: 1, adsorption: 2)        -   3CAA0075 and 3CAA0076 (Composition of the invention)

A sample of the composition of the invention was mixed with distilledwater and a sample was tested either using a Hydro 2000SM unit orMastersizer 3000 (using a Scirocco 2000 unit).

Results

Several batches of the composition of the invention, obtained afterdrying and milling, were tested according to the above-mentioned method.The results are provided in Table 1 below.

TABLE 1 Particle Size Distribution of the composition of the invention(where (D90) corresponds to 90% of the particle size population, and(D4:3) corresponds to the volume moment mean of the particle sizepopulation). PS (D90) PS (D4:3) Ball Mill Reference Product name in μmin μm 3CAA0076 Turmipure Enhanced 30% - Ball Milled 3.3 1.7 3COA0004Organic Turmipure Enhanced 30% - 3.4 1.6 Ball Milled 3COA0004 OrganicTurmipure Enhanced 30% - 3.5 2.1 Ball Milled 3COA0004 Organic TurmipureEnhanced 30% - 2.6 1.6 Ball Milled 3CAA0076 Turmipure Enhanced 30% -Ball Milled 2.4 1.4 3CAA0076 Turmipure Enhanced 30% - Ball Milled 3.51.8 3CAA0076 Turmipure Enhanced 30% - Ball Milled 3.2 1.5 3CAA0076Turmipure Enhanced 30% - Ball Milled 3.1 1.5 3CAA0076 Turmipure Enhanced30% - Ball Milled 2.7 1.3 3CAA0076 Turmipure Enhanced 30% - Ball Milled3.1 1.5 3CAA0076 Turmipure Enhanced 30% - Ball Milled 3.5 1.7 3CAA0076Turmipure Enhanced 30% - Ball Milled 2.7 1.4 3CAA0076 Turmipure Enhanced30% - Ball Milled 4.4 2.0 3CAA0076 Turmipure Enhanced 30% - Ball Milled3.1 1.5 3CAA0076 Turmipure Enhanced 30% - Ball Milled 3.4 1.6 3CAA0076Turmipure Enhanced 30% - Ball Milled 3.2 1.6 3CAA0076 Turmipure Enhanced30% - Ball Milled 3.9 1.7 3CAA0076 Turmipure Enhanced 30% - Ball Milled3.9 1.8 3COA0004 Organic Turmipure Enhanced 30% - 2.9 1.4 Ball Milled3COA0004 Organic Turmipure Enhanced 30% - 3.1 1.4 Ball Milled 3COA0004Organic Turmipure Enhanced 30% - 3.1 1.5 Ball Milled 3COA0004 OrganicTurmipure Enhanced 30% - 3.3 1.5 Ball Milled 3COA0004 Organic TurmipureEnhanced 30% - 3.2 1.5 Ball Milled 3COA0004 Organic Turmipure Enhanced30% - 3.4 1.6 Ball Milled 3COA0004 Organic Turmipure Enhanced 30% - 3.21.6 Ball Milled 3COA0004 Organic Turmipure Enhanced 30% - 3.1 1.4 BallMilled 3COA0004 Organic Turmipure Enhanced 30% - 3 1.5 Ball Milled3COA0004 Organic Turmipure Enhanced 30% - 3.2 1.5 Ball Milled 3COA0004Organic Turmipure Enhanced 30% - 2.9 1.5 Ball Milled 3COA0004 OrganicTurmipure Enhanced 30% - 3.2 1.5 Ball Milled 3COA0004 Organic TurmipureEnhanced 30% - 3.2 1.5 Ball Milled 3COA0004 Organic Turmipure Enhanced30% - 3.1 1.7 Ball Milled 3COA0004 Organic Turmipure Enhanced 30% - 2.91.4 Ball Milled 3COA0004 Organic Turmipure Enhanced 30% - 2.96 1.41 BallMilled 3COA0004 Organic Turmipure Enhanced 30% - 3.39 1.59 Ball Milled3COA0004 Organic Turmipure Enhanced 30% - 3.2 1.5 Ball Milled 3COA0004Organic Turmipure Enhanced 30% - 3 1.4 Ball Milled

Example 5—Morphology of a Composition of the Invention (by ScanningElectron Microscopy, SEM)

For SEM analysis samples were prepared as follow: The composition of theinvention in powder form was deposited on the sample holder by simplydusting. It was followed by metallization of platinum/palladium depositsand then observation and shooting by scanning electron microscopeequipped with X-ray detector in energy dispersion.

The SEM images shown in FIGS. 7, 8 and 9 provide the visualization ofthe composition of the invention.

The composition of the invention shows conjugate self-assembled tospherical micelles with size of +/−170 nm. The roughly sphericalmorphology in SEM analysis corroborated the size measurement analysisdone by dynamic light scattering technique.

From SEM, it can be seen that the particles in the composition of theinvention have clearly shown outer coat of chitosan which was absent inuncoated lecithin nanoparticles. Curcumin was found to be well dispersedin the lecithin core of the nanoparticles. SEM measurements alsocorroborated evidence of roughly spherical geometry and the surfaceroughness indicate surface absorption. It suggests that the drivingforce of this type of adsorption is either direct electrostaticinteraction or ion-ion interaction.

Example 6—Testing the Effect of a Composition of the Invention toEnhance the Bioavailability of Curcuminoids in an In-Vivo Model of theHuman Gastrointestinal Tract and Intestinal Absorptive Cells

The human gastrointestinal tract (GIT) is one of the major entry gatesto the human body. Upon oral ingestion of foods, drinks orpharmaceuticals, the gut is the first site of contact between theingested products and the host. In order to exert their biologicalactivity, compounds have first to pass the stomach where the acidenvironment and the presence of digestive enzymes may lead to chemicalor enzymatic modifications. After leaving the stomach, ingestedcompounds reach the small intestine, in which a major part of the hostmetabolic enzymes are secreted, possibly leading to further enzymaticmodifications. The compound, in its original or modified form, maysubsequently be absorbed and enter circulation, or may further passthrough the intestine. Here, food compounds may have a local biologicalactivity by coming into contact with the complex microbial communitypresent in the terminal ileum (last portion of the small intestine) andthe colon (Alegria et al, 2015).

Human studies are certainly one of the most representative ways to studythe different intestinal processes. However, they are highly labor- andtime-consuming, very costly and do not allow mechanistic studies.

In humans, the intestine can be considered a black box that allowsquantifying the in- and output but investigating the underlyingintestinal processes in their different compartments is difficult due tosampling issues. Moreover, ethical constraints limit the generalapplication of human trials.

Therefore, well-designed in vitro simulation technologies offer a veryuseful alternative for human and animal studies. Being representativefor specific processes, such models enable reproducible in-depth studiesof these processes without ethical constraints. The easier setup andsampling allow medium to high throughput studies at lower costs.Nonetheless, the lack of a physiological host environment is the mostimportant limitation of these models. However, the use of standardizedin vitro cell cultures using human-derived cell lines provide a fast andreproducible way to study the ultimate effects of compounds on theintestinal mucosa. Furthermore, extensive in vitro investigation allowsto carefully design subsequent animal or human studies, thereby savingtime and money.

Carefully designed GIT-simulating in vitro approaches offer an excellenthigh-throughput screening setup to evaluate the putative metabolic fateof selected food ingredients at different concentrations. Suchingredients may be modified or modify the bacterial community in thegut, and therefore, reach the intestinal mucosa intact or in the form ofa modified by-product. Oral bioavailability of dietary compounds isdefined as the fraction of the administered dose able to be absorbed bythe intestinal cells and that is available for use or storage.

Bioavailability of dietary compounds is dependent on many factors,namely on the nutritional and physiological status of the individual, onthe conjugation of the compound with other nutrients and/or bile salts,on the enzymatic degradation of the compound by digestive enzymes, andon the capacity of the gut-associated bacteria to metabolize it. Invitro gastrointestinal model offers the possibility to screen a largeset of molecules in a rapid and cost-effective way in short-termexperiments.

The following approach allows to rapidly assess the intestinal fate ofdietary compounds upon digestion and colon fermentation. This,associated with in vitro cell models that mimic the human intestinalepithelium, allow to investigate the bioavailability of the intact andmodified compounds, thereby increasing both the scientific output andcommercial relevance.

Firstly, short-term screening assays were performed as a tool toevaluate the digestive fate of curcumin-based formulations, withdifferent solubility properties.

The results of these experiments were then applied to Caco-2 cells invitro in order to investigate the bioavailable fraction of the differentformulations, in comparison to their unmodified/undigested forms.

In addition, cellular toxicity was measured in order to compare theputative cytotoxic effects of the different digestive fractions.

The short-term screening assays consisted of the sequential incubation(stomach, small intestine, colon) of a representative dose(s) of theselected lead compounds under simulated conditions for the largeintestine with a representative bacterial inoculum.

An intestinal suspension collected from the ascending colon compartmentof the Simulator of the Human Intestinal Microbial Ecosystem (SHIME) wasused (Van de Wiele et al, 2015).

This inoculum consists of a stable microbial community which is adapted,both in structure and activity, to the environmental conditions whichare present in the proximal colon.

The following curcumin-based formulations/composition were evaluated:

1. A standard curcumin extract (Curcuma longa)—containing a mix of 3curcuminoids (curcumin—75%, demethoxicurcumin (DMC)—15 to 20% andbidemethoxycurcumin (BDMC)—5 to 10%).

2. A control formulation (Turmeric phytosome Thorne product with Meriva®which formulation comprises 18-22% curcuminoids, where the curcumin andsoy lecithin present are formulated in a 1:2 weight ratio (Phytosome),and two parts of microcrystalline cellulose are then added to improveflowability, with an overall content of curcumin in the final product ofaround 20%.)

3. A composition as used in the methods/uses of the invention comprising8.6% turmeric extract (with more than 6% curcuminoids), 15.9% sunfloweroil, 2% quillaja extract, and 73.5% modified starch) (also referred toherein as Form I).

The short-term screening assay consisted on the sequential incubation ofthe three formulations under stomach, small intestine and colonconditions.

The formulations/compositions were tested to achieve a curcuminoidsconcentration of 0.5 g/L in the stomach compartment (the actual amountin mg was calculated based on the % of curcuminoids within eachproduct—as shown in Table 2).

The different formulations/compositions were then incubated for 1 hour(h) at 37° C., pH 2.0, in the presence of pepsin.

The small intestine was then simulated by adding pancreatic enzymes andbile salts and samples were incubated at 37° C. for a total duration of3 h.

Finally, in the third incubation stage, the colon was simulated byadding a representative fecal inoculum collected from the SHIME and arich nutritional media. Colon incubations were carried out at 37° C.,with shaking and under anaerobiosis, over a total duration of 48 h.

Each formulation/composition was tested in triplicate to control forbiological variability.

Note that these experiments were designed in order to respect thespecific residence times of food ingredients in the gastrointestinaltract. Considering the volumes within each compartment, theconcentration of curcuminoids tested was: 0.5 g/L in the stomach, 0.35g/L in the small intestine and 0.1 g/L in the colon. For the celltransport experiments these samples were diluted 10× more.

TABLE 2 Curcumin-based formulations/compositions tested and therespective curcuminoids percentage in the formulation/composition. Thecurcuminoids percentage was taken into account in order to calculate theamount in mg to be added to the stomach compartment. In bold is depictedthe native form. Curcuminoids content % Description Curcumin DMC BDMCTotal Standard Turmeric powder 79.42 14.72 2.03 96.18 extract (95%curcuminoids) Turmeric phytosome (Thorne 13.43 2.70 0.28 16.40 productwith Meriva ®) A composition as used in the 5.50 0.77 0.08 6.35methods/uses of the invention comprising turmeric extract, sunfloweroil, quillaja extract and modified starch

Samples for each formulation/composition were collected at the followingtime points:

-   -   Stomach: 30 min and 60 min    -   Small intestine: 60, 120 and 180 min    -   Colon: 2, 4, 6, 24 and 48 hours

The samples were then analyzed for their curcuminoids content (curcumin,DMC and BDMC) using high pressure liquid chromatography (HPLC) coupledwith mass spectrometry.

A calibration curve was prepared in the range 2-1000 ng/mL for each 3curcuminoids (Phytolab, Vestenbergsgreuth, Germany) adding 54 ppb ofcurcumin-d6 (TLC pharmachem, Ontario, Canada) as an internal standard toensure retention time stability and instrument correction variation.Acetonitrile was used as the diluent for each solution. For freecurcuminoid determination, exactly 450 μL of internal standard solution(60 ng/mL) was loaded over 50 μL of plasma sample into Captiva 96 wellsplate (ND lipids from Agilent). After mixing and filtration the eluateis ready to be injected into LC/MS system. Captiva ND Lipid plates aredesigned to effectively remove phospholipids from plasma. For thedetermination of total conjugated curcuminoid metabolites (glucuronideand sulfate metabolites), 100 μL of plasma sample was mixed with 100 μLof enzyme solution (either glucuronidase 1000 units/mL, Sigma #G7017; orsulfatase, Sigma #S9626, 100 units/mL) for 2 hours at 37° C. After thishydrolysis step, 50 μL of the solution is mixed with 450 μL ofacetonitrile onto Captiva 96 wells plate as well. The sample procedureis the same than for free curcuminoids, mixing and filtering beforeinjection.

LC/MS conditions were then as follows. The autosampler (5° C.) and LCsystem used was an Agilent Infinity 1290 integrated system. Agilent 6420Triple quadrupole mass spectrometer was used during the study, withelectrospray ionization. The metabolites were eluted from the BEH ShieldRP 18 column (100×2.1, 1.7 μm; Waters) with a mobile phase consisting of0.1% formic acid in water in HPLC grade (solvent A) and 0.1% formic acidin acetonitrile (solvent B), at a flow rate of 0.5 mL/min. The elutionwas in gradient from 40-80% B at 0-6 min. The injection volume was 2 μLfor standard and samples. For each reference compound, a relevanttransition of the precursor-to-product ions were detected with theutilization of the multiple reaction monitoring (MRM) mode. For each ofthe 3 analytes was determined in MS1 full scan tests and the productions in MS/MS experiments. MRM transitions of each analyte wereoptimized using direct infusion and Optimizer B.08.00 workstationsoftware solution (Agilent technologies, Santa Clara, Calif., USA). SeeTable 2a for the optimal selected conditions. The mass spectrometerparameters were set as follows: ESI source both in negative and positivemode; drying gas (N2) flow rate, 10 L/min; gas temperature, 350° C.;nebulizer, 40 psi; and capillary, 4.0 kV. The MS system fully calibratedprior to running according to manufacturer's guidelines. Data analysiswere carried out on Agilent MassHunter Quantitative/Qualitative analysisB.07.00 (Agilent technologies, Santa Clara, Calif., USA).

TABLE 2a Retention times (Tr), multiple reaction monitoring (MRM)transitions, and optimized tandem mass spectrometry (MS/MS) detectionparameters of 3 curcuminoids and internal standard. Prec. Prod. Ion Q1ions Q3 Dwell Rt Mass Mass Time Frag CE Compounds (min) ISTD? (Da) (Da)(ms) (V) (V) Polarity Curcumine 3.25 yes 375.2 291.1 50 110 12 positived6 180.1 110 18 Curcumine 3.29 No 369.1 285.1 98 13 177.1 98 25 DMC 3.49No 339.1 255.1 110 12 177.1 110 16 BDMC 3.68 No 309.1 225.1 110 12 119.1110 36

Table 3 depicts the concentration in curcuminoids obtained among theintestinal tract compartments during digestion.

Surprisingly the concentrations after digestion in the stomach after 60min and the small intestine after 120 min and 180 min for thecomposition as used in the methods/uses of the invention were superiorthan the ones obtained for the standard turmeric powder extract,demonstrating a better resistance to digestion for the composition asused in the methods/uses of the invention in comparison to the standardextract. Also, the concentrations after digestion in the stomach after60 min and the small intestine after 120 min and 180 min for thecomposition as used in the methods/uses of the invention were higherthan the ones of the comparator Turmeric phytosome formulation,demonstrating a better resistance to digestion for the composition asused in the methods/uses of the invention in comparison to the Turmericphytosome comparator.

Table 4 shows the percentage of curcuminoids that remained in theintestinal compartments after digestion according to the initialconcentrations (0.5 g/l or 500 mg/l of curcuminoids in the stomachcompartment at the beginning of the experiments). The results clearlyshow that surprisingly, curcuminoids coming from the composition as usedin the methods/uses of the invention had a far better resistance todigestion in the stomach and small intestine in comparison tocurcuminoids coming from the standard turmeric extract and compositionas used in the methods/uses of the invention are more protected fromdegradation during digestion after oral consumption then curcuminoidsfrom the standard extract or the Turmeric phytosome formulation and thatthere are much more curcuminoids accessible for absorption in the smallintestine compartment after oral consumption of the composition as usedin the methods/uses of the invention than oral consumption of thestandard extract or the turmeric phytosome formulation.

TABLE 3 Concentration of curcuminoids in the different compartments ofthe gastro-intestinal tract during the digestion process for the threeformulations Concentration Turmeric phytosome (Thorne The composition asused in the after digestion Standard Turmeric powder extract productwith Meriva ®) methods/uses of the invention (ppm or mg/l) Curcumin DMCBDMC Total Curcumin DMC BDMC Total Curcumin DMC BDMC Total Initial412.915 76.511 10.573 500.000 409.451 82.165 8.384 500.000 433.01860.678 6.304 500.000 412.915 76.511 10.573 500.000 409.451 82.165 8.384500.000 433.018 60.678 6.304 500.000 412.915 76.511 10.573 500.000409.451 82.165 8.384 500.000 433.018 60.678 6.304 500.000 ST60 min239.880 45.610 6.523 292.013 ND 398.600 81.901 11.880 492.381 162.43031.080 5.108 198.618 345.510 71.428 10.983 427.921 125.390 27.570 4.564157.524 426.930 88.494 12.595 528.019 Mean 175.900 34.753 5.399 216.052390.347 80.608 11.819 482.774 SD 58.421 9.565 1.011 68.919 41.333 8.6060.808 50.736 SI 120 min 36.417 8.723 3.772 48.912 107.857 23.464 5.250136.571 325.371 58.626 11.509 395.506 53.372 11.500 4.407 69.279 108.57123.957 5.200 137.729 342.014 66.726 10.613 419.353 39.145 9.041 3.94052.126 109.286 31.286 6.957 147.529 312.314 61.350 9.924 383.588 Mean42.978 9.755 4.040 56.772 108.571 26.236 5.802 140.610 326.567 62.23410.682 399.482 SD 9.104 1.520 0.329 10.950 0.714 4.380 1.000 6.02014.886 4.122 0.795 18.211 SI 180 min 36.188 8.150 3.699 48.037 110.00024.564 5.057 139.621 276.500 54.060 9.117 339.677 34.933 8.500 3.86147.294 110.714 28.243 5.793 144.750 236.500 46.564 8.105 291.169 40.2759.211 4.433 53.919 61.329 29.569 6.604 97.501 301.729 58.411 10.343370.483 Mean 37.132 8.620 3.998 49.750 94.014 27.459 5.818 127.291271.576 53.012 9.188 333.776 SD 2.793 0.541 0.386 3.629 28.309 2.5930.774 25.926 32.892 5.993 1.121 39.985 Colon 2 h 15.623 11.508 9.98937.119 7.521 6.810 2.280 16.611 5.248 3.554 1.647 10.449 12.307 9.3377.965 29.609 8.137 9.334 4.403 21.873 5.783 3.660 1.497 10.939 11.89611.535 11.990 35.420 6.263 6.628 2.742 15.632 4.820 3.443 1.731 9.994Mean 13.275 10.793 9.981 34.049 7.307 7.590 3.141 18.039 5.284 3.5521.625 10.461 SD 2.043 1.261 2.013 3.938 0.955 1.512 1.116 3.357 0.4820.108 0.119 0.473 Colon 24 h 11.364 5.136 1.785 18.284 7.815 4.405 1.17113.391 4.408 1.744 0.551 6.703 10.001 4.828 1.820 16.649 7.187 4.3921.154 12.732 4.427 1.788 0.569 6.783 9.297 4.358 1.249 14.903 0.8960.734 0.218 1.847 4.073 1.460 0.292 5.824 Mean 10.220 4.774 1.618 16.6125.299 3.177 0.847 9.323 4.303 1.664 0.470 6.437 SD 1.051 0.392 0.3201.691 3.826 2.116 0.545 6.483 0.199 0.178 0.155 0.532 Colon 48 h 6.4692.303 0.549 9.320 5.158 2.926 0.727 8.811 2.453 0.870 0.199 3.521 4.9922.403 0.697 8.091 3.750 2.423 0.614 6.786 2.976 1.197 0.303 4.476 6.3832.858 0.837 10.077 4.438 2.488 0.609 7.535 3.285 1.192 0.315 4.792 Mean5.948 2.521 0.694 9.163 4.448 2.612 0.650 7.711 2.905 1.086 0.272 4.263SD 0.829 0.296 0.144 1.002 0.704 0.274 0.067 1.024 0.420 0.188 0.0640.661 Each formulation was tested in triplicate; the results present themean and SD of the 3 experiments. DMC: Demethoxycurcumin; BDMC:Bisdemethoxycurcumin; ND: Not determined; SD: Standard deviation; ST:Stomach; SI: Small Intestine

TABLE 4 Resistance to Gastro-intestinal (GIT) digestion: percentage ofcurcuminoids that remained in the intestinal compartments afterdigestion according to the initial concentration Turmeric Thecomposition as Resistance to GIT phytosome (Thorne used in the digestion(% of initial Standard Turmeric product with methods/uses ofconcentration) powder extract Meriva ®) the invention Stomach 60 min43.21 ± 13.78% ND 96.55 ± 10.15% SI 120 min 11.35 ± 2.19%  28.12 ±1.20%  79.90 ± 3.64%  SI 180 min 9.9 5 ± 0.73%  25.46 ± 5.19%  66.76 ±8.00%  Colon 2 h 6.81 ± 0.79% 3.61 ± 0.67% 2.09 ± 0.09% Colon 24 h 3.32± 0.34% 1.86 ± 1.30% 1.29 ± 0.11% Colon 48 h 1.83 ± 0.20% 1.54 ± 0.20%0.85 ± 0.13% The data shows mean ± SD of the percentage of curcuminoidsconcentration in the different compartments and the different timesafter digestion in comparison to the initial concentration.

The following samples were also collected for the transport experimentson Caco-2 cells:

-   -   Small intestine: 120 and 180 min

The pH of the samples to be applied to the cells was adjusted to 6.5prior to use.

Caco-2 cells are widely used as a cellular model for intestinalfunction, as they are able to spontaneously differentiate intoenterocyte-like cells in culture. When cultured in semi-permeablesupports, these cells develop into a functional polarized monolayer thatresembles the intestinal epithelia, with the presence of apicalbrush-border enzymes and microvilli. Therefore, because they acquire inculture morphological and functional characteristics of matureenterocytes, they are considered as the “gold standard” model fortransport experiments (Sambuy et al, 2002).

Caco-2 cells (ATCC) were seeded in 12-transwell inserts (0.4 μm) at adensity of 0.9×105 cells/cm², corresponding to 1×105 cells/insert. Cellswere let differentiate until a functional monolayer was reached (21days); the apical (600 μL) and the basolateral (1500 μL) media werereplenished three times a week. On the day of the experiment, thebarrier function was assessed by measuring the transepithelialelectrical resistance (TEER) of the monolayer. Cells were washed withHBSS to remove traces of media, and 2 mL of transport buffer (TB) wasadded to the basolateral side. The samples collected from the short-termexperiments were diluted in transport buffer at 1:10 (v/v) ratio andgiven apically to the cells (600 μL). All products were also testedunprocessed and the powders diluted in TB at a concentration of 0.025mg/mL (the final theoretical concentrations of curcuminoids tested forall formulations can be seen in Table 2a). These dilutions were preparedfrom stock solutions (250 mg/mL) prepared in HBSS, except for thestandard turmeric extract, which was dissolved in DMSO, due to its poorsolubility. As control wells, we have used colon samples (48 hincubation) diluted 1:10 (v/v) in TB obtained by running during theshort-term experiments a blank (no curcumin). The transport buffer (TB)consisted of HBSS (pH 7.4) supplemented with 10 mM HEPES, 25 mMD-Glucose and 1× antibiotic-antimycotic. Cells were incubated for atotal duration of 4 h at 37° C.

The following samples were collected:

1. Diluted samples that were used to stimulate the cells (500 μL). Thesecorrespond to a 0 h time point, as it contains the diluted samplesbefore being given to the cells unprocessed formulations diluted in TBat a concentration of 0.025 mg/mL were also shipped.

2. Samples from the apical side collected after 2 h and 4 h ofincubation (250 μL each).

3. Samples from the basolateral side collected after 2 h (800 μL) and 4h (1000 μL) of incubation.

4. Samples from the cells after 4 h of incubation. These correspond tothe fraction which has been uptaken inside the cells. Briefly, ice-coldPBS 1× was added to the cells to terminate the transport. Then, thecells were washed once more with PBS 1× to remove traces of productwhich has not been internalized, and cells were permeabilized with asolution of PBS 1× containing 20% of ethanol and 0.1% Tween-20 (600 μL);after 20 min in this solution, the cells were collected into a 1.5 mLtube and disrupted and homogenized with the help of a syringe and a 21 Gneedle. The tubes were centrifuged and the supernatant transferred intoa new tube (450 μL).

All samples were stored at −20° C. until HPLC analysis.

In order to evaluate the cytotoxicity of the different samples appliedto Caco-2 cells, lactate dehydrogenase (LDH) released by Caco-2 cells onthe apical side (after 4 h of incubation) was evaluated by using aLDH-Activity Kit. LDH is released into the supernatant by cells uponmembrane injury, and is therefore a marker for cell death.

Statistical analysis was done using a one-way ANOVA followed by aDunnett's post-hoc multiple comparison test. (*), (**) and (***)correspond to significances at p<0.05, p<0.01 and p<0.001, respectively.

As shown in FIG. 10 to 15, the control wells (TB+colon 48 h) show a LDHactivity around 1.0. As it is possible to see, for all products, boththe undigested form as well as the stomach samples collected after 60min shown the highest LDH activity when compared to the control.

In contrast, both small intestine and colon samples show levelscomparable to the control or lower. These results demonstrated thatexcept from samples coming from the stomach, all samples exhibited notoxicity on Caco-2 cells and results of the assays testing transport andbioavailability of curcuminoids from the samples in Caco-2 cells couldbe exploited and judged as valid because obtained on viable cells.

Samples from the apical, basolateral and intracellular compartments ofCaco-2 cells incubated with either undigested products or with samplescoming from the small intestine (120 min or 180 min) were furtheranalyzed for their curcuminoids content (curcumin, DMC and BDMC) andtheir relative metabolites content (Curcumin sulfate, curcumineglucuronide, DMC sulfate and DMC glucuronide, BDMC sulfate and BDMCglucuronide) as Caco-2 cells are known to expressUDP-Glucuronosyltransferases and sulfotransferases (Siissalo S, Zhang H,Stilgenbauer E, Kaukonen A M, Hirvonen J, Finel M. The expression ofmost UDP-glucuronosyltransferases (UGTs) is increased significantlyduring Caco-2 cell differentiation, whereas UGT1A6 is highly expressedalso in undifferentiated cells. Drug Metab Dispos. 2008 November;36(11):2331-6) therefore being able to metabolize curcumin, DMC and BDMCin their glucuronide or sulfate metabolites (Dempe J S, Scheerle R K,Pfeiffer E, Metzler M. Metabolism and permeability of curcumin incultured Caco-2 cells. Mol Nutr Food Res. 2013 September; 57(9):1543-9).

The apparent permeability coefficient (P_(app)) values for the apical tobasolateral transition were calculated according to Artursson andKarlsson using the formula:

P _(app) [cm/s]=(Vapi/(A*t))*(Cbaso/Capi)

where Vapi is the volume of the apical compartment (0.6 mL), A is thesurface area of the monolayer (1.131 cm²), t is the time (s), Cbaso isthe concentration (ppm) of the total curcuminoids and their metabolitesin the basolateral compartment (sum of parent compound and metabolites),and Capi is the initial concentration (ppm) of total curcuminoids in theapical compartment.

The table 5 depicts the P_(app) values for different time intervalsafter apical exposure of Caco-2 cells to the standard extract or the 2different formulations (Turmeric phytosome or the composition as used inthe methods/uses of the invention).

TABLE 5 P_(app) values of total curcuminoids and their metabolites(expressed as 10⁻⁷ cm/s) calculated for different time intervals afterapical exposure of Caco-2 cells to the standard extract or the 2different formulations After 2 h After 4 h P_(app) (×10⁻⁷ cm/s) ofincubation of incubation Standard Turmeric powder 2.13 ± 0.23 1.10 ±0.07 extract Turmeric phytosome 9.94 ± 0.20 5.33 ± 0.25 (Thorne productwith (4.7) (4.8) Meriva ®) The composition as used 41.01 ± 1.37  22.33 ±0.43  in the methods/uses of the (19.3) (20.3) invention with turmeric[4.1] [4.2] extract, sunflower oil, quillaja extract and modified starchThe data shows mean ± SD. The fold increase in P_(app) relative tostandard extract is shown into brackets ( ). The fold increase inP_(app) relative to turmeric phytosome formulation is shown in squarebrackets [ ].

As shown in table 5, the apparent permeability coefficient (P_(app))values for the apical to basolateral transition was surprisingly higherfor the composition as used in the methods/uses of the invention thenfor the standard turmeric extract, with a fold increase of 19.3 and 20.3in P_(app) value relative to standard turmeric extract respectively at 2h and 4 h.

The apparent permeability coefficient (P_(app)) value for the apical tobasolateral transition was also higher for the Turmeric phytosomeformulation, which was used as a positive control for an enhancedbioavailability formulation, then for the standard turmeric extract,with a fold increase of 4.7 and 4.8 in P_(app) relative to standardturmeric extract respectively at 2 h and 4 h. But the results show thatabsorption of curcuminoids by Caco-2 absorptive cells was greater forthe composition as used in the methods/uses of the invention (P_(app)value 4.1-fold and 4.2-fold superior at 2 h and 4 h respectively) incomparison to the comparator turmeric phytosome formulation.

Table 6 depicts the P_(app) values after apical exposure of Caco-2 cellsto the small intestine digestion samples (120 or 180 min) of thestandard extract or the 2 different formulations (Turmeric phytosome orthe composition as used in the methods/uses of the invention) using thequantified concentrations of curcuminoids in the small intestinecompartments at 120 min or 180 min as Capi. It reflects the absorptioncapacity of curcuminoids from the digested formulation by the cells.When standard extract or formulations have been digested in the stomachand small intestine compartments and therefore samples coming from thesmall intestine (120 min or 180 min) are used to measure the absorptionof curcuminoids by Caco-2 cells, we demonstrated that absorption ofcurcuminoids by Caco-2 absorptive cells was greater for the compositionas used in the methods/uses of the invention (P_(app) value 1.8-fold and16.4-fold higher for the small intestine sample at 120 min or 180 minrespectively) in comparison to the turmeric phytosome formulation.

Table 7 depicts the P_(app) values after apical exposure of Caco-2 cellsto the small intestine digestion samples (120 or 180 min) of thestandard extract or the 2 different formulations (Turmeric phytosome orthe composition as used in the methods/uses of the invention) using thetheoretical concentrations of curcuminoids in the small intestinecompartments at 120 min or 180 min as Capi in order to take into accountnot only the absorptive capacity of the cells but also resistance to thedigestive process. We demonstrated from those data that the level ofcurcuminoids that can reach the basolateral compartment (that mimicsblood circulation) after gastrointestinal digestion and absorption byCaco-2 cells during 120 min and 180 min are much higher for thecomposition as used in the methods/uses of the invention in comparisonto the standard turmeric extract turmeric (P_(app) value 2.0-fold and1.8-fold higher for the small intestine sample at 120 min or 180 minrespectively) and in comparison to the phytosome formulation (P_(app)value 3.4-fold and 7.1-fold higher for the small intestine sample at 120min or 180 min respectively).

TABLE 6 P_(app) values of total curcuminoids and their metabolites afterapical exposure of Caco-2 cells to the small intestine digestion samples(120 or 180 min) of the standard extract or the 2 different formulationsAfter 2 h of incubation of SI digestion SI digestion P_(app) (×10⁻⁸cm/s) samples 120 min samples 180 min Standard Turmeric powder extract2.42 ± 1.09 7.19 ± 7.70 Turmeric phytosome (Thorne 0.59 ± 0.08 0.19 ±0.06 product with Meriva ®) The composition as used in the 1.08 ± 0.543.08 ± 1.03 methods/uses of the invention with (1.8) (16.4) turmericextract, sunflower oil, quillaja extract and modified starch The datashows mean ± SD. The fold increase in P_(app) relative to turmericphytosome formulation is shown into brackets ( ). The P_(app) values arecalculated using the quantified concentrations of curcuminoids in thesmall intestine compartments at 120 min or 180 min as Capi.

TABLE 7 P_(app) values of total curcuminoids and their metabolites afterapical exposure of Caco-2 cells to the small intestine digestion samples(120 or 180 min) of the standard extract or the 2 different formulationsAfter 2 h of incubation of SI digestion SI digestion P_(app) (×10⁻⁹cm/s)samples 120 min samples 180 min Standard Turmeric powder extract 2.59 ±0.80 6.90 ± 0.74 Turmeric phytosome (Thorne 1.54 ± 0.04 1.79 ± 0.02product with Meriva ®) the composition as used in the 5.30 ± 2.44 12.65± 0.36 methods/uses of the invention with (2.0) (1.8) turmeric extract,sunflower oil, [3.4] [7.1] quillaja extract and modified starch The datashows mean ± SD. The fold increase in P_(app) relative to standardextract is shown into brackets ( ). The fold increase in P_(app)relative to turmeric phytosome formulation is shown in square brackets []. The P_(app) values are calculated using the theoreticalconcentrations of curcuminoids in the small intestine compartments at120 min or 180 min as Capi.

Example 6—Test the Effect of a Composition of the Invention to Enhancethe Bioavailability of Curcuminoids Through Comparative PharmacokineticStudies In-Vivo in Mice

In view of the results obtained in the in vitro model which showed thatthe composition as used in the methods/uses of the invention showedbetter resistance to gastrointestinal digestion and better absorptionthrough intestinal cells, it is postulated that the composition as usedin the methods/uses of the invention (i.e. a composition comprising 8.6%turmeric extract (comprising more than 6% curcuminoids), 15.9% sunfloweroil, 2% quillaja extract, and 73.5% modified starch), will improve thebioavailability of curcuminoids in comparison to a standard turmericextract in mice.

Therefore, a comparative pharmacokinetic study was conducted in mice.

Adult male C57Bl/6J Rj mice from Janvier Labs (St-Berthevin, France), at5 weeks of age at receipt, were housed collectively in standard plasticcages (n=4/cage). All animals had ad libitum access to water andstandard pellet food (pellet A04; SAFE, Villemoisson-sur-Orge, France),and were maintained in a temperature—(24.0 to 26.0° C.) andhumidity-(40.0 to 50.0%) controlled room on a 12-h light (07:00 AM-07:00PM)/12-h dark cycle.

All animals were acclimatized to their new environment for one weekfollowing receipt. In order to ensure both a correct acclimatization anda standard growth curve, the global food intake and the body weight ofthe animals were evaluated twice per week. Following thisacclimatization period, mice were habituated to receive a daily per osadministration of vehicle (Carboxymethylcellulose sodium salt 1% (w/v)dissolved in distillated water at room temperature, CMC; Ref #C4888,Batch number: SLBB5612V, SIGMA ALDRICH, St Quentin Fallavier, FRANCE)for six days before the treatment. During this habituation period, theglobal food intake and the body weight of the animals were measureddaily. These measures allowed to be sure of an optimal habituation ofthe animals to both the injection procedures and the manipulation by theexperimenters.

During the acclimatization and habituation periods, mice were allowed adlibitum access to a preweighed quantity of fresh food pellets (pelletA04; SAFE, Villemoisson-sur-Orge, France). The remaining food wasweighed the next day of measure. Using a precision scale (THB-600G, PMCMillot; precision±0.01 g), the global food intake per cage (08:40-09:20AM) was determined by subtracting the remaining food to the preweighedquantity of food. The mean daily food intake was obtained by dividingthis value by the number of days separating two measures and by thenumber of animals of each cage. At each body weight measurement, micewere weighed in the morning (08:40-09:20 AM).

The day prior the treatment (last day of the habituation period), 120mice were fasted in the evening (17:40-18:20 PM). The day after, mice(n=40 per formulation) received an acute treatment by oral gavage (30ml/kg) in the morning (08:00-09:50 AM) with a standard turmeric powderextract, the Tumeric phytosome formulation as a comparator or thecomposition as used in the methods/uses of the invention (i.e. acomposition comprising 8.6% turmeric extract (with more than 6%curcuminoids), 15.9% sunflower oil, 2% quillaja extract, and 73.5%modified starch).

An appropriate volume of Vehicle (CMC 1% dissolved in distilled water)was added in a suitable recipient under agitation and the pH wasadjusted to 5.5. An appropriate amount of pre-weighted formulation wasgradually added to the vehicle under constant agitation. Oncehomogeneous, the pH of the obtained suspension was measured and adjusted5.5 if needed. In order to avoid any degradation of the curcuminoids,the final suspension was systematically administered in 1 h followingpreparation. Doses were calculated to fed animals with 300 mg/kg oftotal curcuminoids (see table 8). This dosage in mice is equivalent to21.37 mg/kg in humans and 1282 mg assuming a 60 kg human—formula from(U.S. Department of Health and Human Services, Food and DrugAdministration, Center for Drug Evaluation and Research (CDER). Guidancefor Industry Estimating the Maximum Safe Starting Dose in InitialClinical Trials for Therapeutics in Adult Healthy Volunteers. 2005);Human Equivalent Dose (mg/kg)=animal dose in mg/kg×(animal weight inkg/human weight in kg)^(0.33). Doses were adjusted to the body weightmeasured just before fasting. In order to avoid any impact of feedingand drinking behavior on intestinal absorption after oral gavage withthe formulation, animals were water- and food-deprived during the first12 h following the treatment.

TABLE 8 Curcuminoids content of the standard turmeric extract and the 2formulations and the respective concentration of the suspension used forproduct administration to mice at 300 mg/kg body weight of curcuminoidsin the first in vivo study Curcuminoids C. ° of dosing content solution(mg of Formulation (g/100 g) formulation/ml) Standard Turmeric powder96.18 10.40 extract (95% curcuminoids) Turmeric phytosome 16.40 60.98(Thorne product with Meriva ®) The composition as used in 6.345 157.60the methods/uses of the invention with turmeric extract, sunflower oil,quillaja extract and modified starch

Blood was sampled at 0.5-, 1 h-, 2 h-, 4 h-, 6 h-, 8 h-, 12 h- or 24h-post-dosing by cardiac puncture on anaesthetized mice (n=5/timepoint/formulation). Anesthesia was performed by intraperitonealinjection of a mixture of Ketamine/Xylazine (100 mg/kg and 15 mg/kg,respectively). For cardiac puncture, a 26 G syringe was inserted betweenthe eighth and the tenth sternal rib, with an angle of 450 with thelongitudinal axis formed by the body of the animal, in order to directlypenetrate the left heart ventricle. Blood was then gently drawn toobtain a final volume of 0.6-1 ml. For the interests of thebioanalytical method, blood was thereafter transferred into an Eppendorftube, mixed with heparin sulfate (200 U·l/ml of blood) and gentlyagitated. All samples were centrifuged during 15 minutes at 3000 g and4° C. within 30 minutes after blood collection to isolate plasma. Plasma(supernatant) was aliquoted in a new 0.5 ml Eppendorf. The aliquots ofplasma were frozen at −80° C. within 1 hour after centrifugation.

Plasmatic dosages of parent curcuminoids (curcumin, DMC or BDMC) andtheir relative metabolites (Curcumin glucuronide and sulfate, DMCglucuronide and sulfate, BDMC glucuronide and sulfate, THC, THCglucuronide and sulfate, HHC, HHC glucuronide and sulfate) wereperformed by a LC-MS-MS method. A calibration curve was prepared in therange 2-1000 ng/mL for each 5 curcuminoids (Phytolab, Vestenbergsgreuth,Germany) adding 54 ppb of curcumin-d6 (TLC pharmachem, Ontario, Canada)as an internal standard to ensure retention time stability andinstrument correction variation. Acetonitrile was used as the diluentfor each solution. For free curcuminoid determination, exactly 450 μL ofinternal standard solution (60 ng/mL) was loaded over 50 μL of plasmasample into Captiva 96 wells plate (ND lipids from Agilent). Aftermixing and filtration the eluate is ready to be injected into LC/MSsystem. Captiva ND Lipid plates are designed to effectively removephospholipids from plasma. For the determination of total conjugatedcurcuminoid metabolites (glucuronide and sulfate metabolites), 100 μL ofplasma sample was mixed with 100 μL of enzyme solution (eitherglucuronidase 1000 units/mL, Sigma #G7017; or sulfatase, Sigma #S9626,100 units/ml) for 2 hours at 37° C. After this hydrolysis step, 50 μL ofthe solution is mixed with 450 μL of acetonitrile onto Captiva 96 wellsplate as well. The sample procedure is the same than for freecurcuminoids, mixing and filtering before injection.

LC/MS conditions were then as follows. The autosampler (5° C.) and LCsystem used was an Agilent Infinity 1290 integrated system. Agilent 6420Triple quadrupole mass spectrometer was used during the study, withelectrospray ionization. The metabolites were eluted from the BEH ShieldRP 18 column (100×2.1, 1.7 μm; Waters) with a mobile phase consisting of0.1% formic acid in water in HPLC grade (solvent A) and 0.1% formic acidin acetonitrile (solvent B), at a flow rate of 0.5 mL/min. The elutionwas in gradient from 40-80% B at 0-6 min. The injection volume was 2 μLfor standard and samples. For each reference compound, a relevanttransition of the precursor-to-product ions were detected with theutilization of the multiple reaction monitoring (MRM) mode. For each ofthe 5 analytes was determined in MS1 full scan tests and the productions in MS/MS experiments. MRM transitions of each analyte wereoptimized using direct infusion and Optimizer B.08.00 workstationsoftware solution (Agilent technologies, Santa Clara, Calif., USA). SeeTable 9 for the optimal selected conditions. The mass spectrometerparameters were set as follows: ESI source both in negative and positivemode; drying gas (N2) flow rate, 10 L/min; gas temperature, 350° C.;nebulizer, 40 psi; and capillary, 4.0 kV. The MS system fully calibratedprior to running according to manufacturer's guidelines. Data analysiswere carried out on Agilent MassHunter Quantitative/Qualitative analysisB.07.00 (Agilent technologies, Santa Clara, Calif., USA).

For the three formulations/compositions tested, the kinetic of plasmaconcentration of each curcuminoid compound was determined between 0.5and 12 h post-treatment by calculating the mean±SEM plasmaticconcentration at each time point of blood collection. Thepharmacokinetic parameters T1/2 (half-life), Cmax, Tmax, AUC(0-12 h) andAUC(0-∞) were determined from the 0-12 h kinetic by a non-compartmentalanalysis using PKSolver. PKSolver is a menu-driven add-in program forMicrosoft Excel written in Visual Basic for Applications (VBA), forsolving problems in pharmacokinetic (Zhang et al., 2010). The whole dataare represented as mean±SEM. Statistical analyses were performed withthe Statview 5.0.1 (Statview software, Cary, N.C., USA) and the Excel2013 programs. Data were analyzed by a Student's t-test at each timepoint. The risk a was fixed at 0.05.

TABLE 9 Retention times (Tr), multiple reaction monitoring (MRM)transitions, and optimized tandem mass spectrometry (MS/MS) detectionparameters of curcuminoids, tetrahydrocurcumin and hexahydrocurcumin andinternal standard. Prec. Ion Prod ions. Dwell Rt Q1 Mass Q3 Mass TimeFrag CE Compounds (min) ISTD? (Da) (Da) (ms) (V) (V) Polarity HHC 1.07No 373.2 179 200 118 12 negative THC 2.04 No 371.1 235.1 200 100 10negative 193.2 100 21 Curcumine 3.25 yes 375.2 291.1 50 110 12 positived6 180.1 110 18 Curcumine 3.29 No 369.1 285.1 98 13 177.1 98 25 DMC 3.49No 339.1 255.1 110 12 177.1 110 16 BDMC 3.68 No 309.1 225.1 110 12 119.1110 36

During the two successive periods of acclimatization (J1 to J7) andhabituation (J8 to J14), the 24 h-food intake and the body weight ofmice were regularly measured in order to ensure both a correctacclimatization and a standard growth curve before treatment. For thepresent study, mice were housed at four per cages, each of them beingused for blood sampling at a same time point after treatment with one ofthe three formulations. As a consequence, the food intake and bodyweight data were first analyzed per group of 15 mice that have beensacrificed at a same time point (8 groups; 5 mice/timepoint/formulation). FIGS. 16 and 17 respectively depicts food intake andbody weight of mice during the acclimatization and habituation periodbefore treatment administration; the different groups showed classicalbody weight curve and food intake before treatment. It should be notedthat the strong decrease in body weight observed in all groups at J15(FIG. 17) resulted from the overnight fasting performed the night beforetreatment. These results confirmed that all mice used in this experimenthad the same behavior and could be compared as expected.

FIG. 18 depicts the pharmacokinetic profile with concentration of thetotal curcuminoids (sum of curcumin, DMC, BDMC and their relativemetabolites curcumin glucuronide sulfate, DMC glucuronide and sulfate,BDMC glucuronide and sulfate, THC, THC glucuronide and sulfate, HHC, HHCglucuronide and sulfate) obtained at each time point in mice after oraladministration (300 mg/kg bw of curcuminoids) of the Turmeric phytosomeformulation and the standard extract formulation. The plasmaconcentration of total curcuminoids for the standard turmeric extractonly reached a maximum of 12.9 ppm at 1 h and was below 10 ppm at allother time points although the turmeric phytosome formulation enabledplasma concentration of total curcuminoids to reach 41.5 ppm (μg/ml)after 30 min and was significantly superior to the one obtained for thestandard at each time point except 24 h. Turmeric phystosomedemonstrated a 3.2-fold increase in total curcuminoids Cmax, a 3.9-foldincrease in AUC compared to standard turmeric extract. These resultsvalidated the use of the Turmeric phytosome formulation to enhance thebioavailability of curcuminoids and as a positive control and validatedthe relevance of our in vivo model to test the capacity of differentformulations to enhance the bioavailability of curcuminoids against astandard turmeric extract.

A table containing the Mean values±SEM for each time point shown asTable 10. The numbers in brackets located next to these values indicatethe number of sample which presented a positive value on the totalnumber of samples. The result of statistical comparisons are also shownin the same table. Table 11 contains the PK parameters obtained from thenon-compartmental analysis using PKSolver software. The percentage ofvariation between groups is also indicated (% Var°). Data arerepresented as mean±SEM.

Total curcuminoids plasmatic levels - Mean ± SEM Standard extractTurmeric phytosome P 0.5 h 9.71 ± 1.56 (5/5) 41.53 ± 7.69 (5/5) 0.0037  1 h 12.95 ± 1.56 (5/5) 34.00 ± 4.28 (5/5) 0.0022   2 h 7.10 ± 1.56(4/4) 24.69 ± 2.41 (5/5) 0.0005   4 h 4.33 ± 1.56 (4/4) 14.31 ± 1.12(5/5) 0.0003   6 h 3.22 ± 1.56 (5/5) 11.59 ± 1.55 (5/5) 0.0007   8 h2.63 ± 1.56 (5/5) 15.03 ± 3.72 (5/5) 0.0110  12 h 0.55 ± 1.56 (4/4) 6.86± 1.80 (5/5) 0.0177  24 h 1.30 ± 1.56 (4/4) 1.44 ± 0.63 (5/5) 0.8709

PK parameters - Total curcuminoids Standard extract Turmeric phytosome %Var° t½ (h) 2.688208 4.926631161 183.2682 Tmax (h) 1 0.5 50 Cmax (ppm)12.95494767 41.52686492 320.5483 AUC 0-t 49.29857342 193.9071934393.3323 (ppm × h) AUC 0-inf 51.41308527 242.667998 471.9966 (ppm × h)

Tables 10 and 11: Showing the Mean values±SEM and the PK parametersobtained from the non-compartmental analysis using PKSolver software foreach time point shown in FIG. 18.

FIG. 19 depicts the pharmacokinetic profile with concentration of thetotal curcuminoids (sum of curcumin, DMC, BDMC and their relativemetabolites curcumin glucuronide sulfate, DMC glucuronide and sulfate,BDMC glucuronide and sulfate, THC, THC glucuronide and sulfate, HHC, HHCglucuronide and sulfate) obtained at each time pointin mice after oraladministration (300 mg/kg bw of curcuminoids) of the mixture comprisingcurcumin, quillaja, oil and modified starch (Example 2 form 1) and thestandard extract formulation. The results showed that the composition asused in the methods/uses of the invention could increase significantlytotal curcuminoids concentration from 0.5 h to 24 h in comparison tostandard turmeric extract. The composition as used in the methods/usesof the invention demonstrated a 1.8-fold increase in total curcuminoidsCmax and a 2.2-fold increase in AUC.

A table containing the Mean values±SEM for each time point is shown asTable 12. The numbers in brackets located next to these values indicatethe number of sample which presented a positive value on the totalnumber of samples. The result of statistical comparisons are also shownin the same table. A table containing the PK parameters obtained fromthe non-compartmental analysis using PKSolver software is presentedTable 13. The percentage of variation between groups is also indicated(% Var°). Data are represented as mean±SEM.

Total curcuminoids plasmatic levels - Mean ± SEM Standard extract Testformulation P 0.5 h 9.71 ± 1.56 (5/5) 18.90 ± 2.45 (5/5) 0.0133   1 h12.95 ± 1.56 (5/5) 22.90 ± 2.45 (5/5) 0.0171   2 h 7.10 ± 1.56 (4/4)19.90 ± 2.45 (5/5) 0.0093   4 h 4.33 ± 1.56 (4/4) 8.49 ± 2.45 (5/5)0.0302   6 h 3.22 ± 1.56 (5/5) 8.67 ± 2.45 (5/5) 0.0012   8 h 2.63 ±1.56 (5/5) 5.11 ± 2.45 (5/5) 0.1123  12 h 0.55 ± 1.56 (4/4) 1.86 ± 2.45(5/5) 0.3241  24 h 1.30 ± 1.56 (4/4) 3.36 ± 2.45 (4/4) 0.1759

PK parameters ± Total curcuminoids Standard extract Test formulation %Var° t½ (h) 2.688208 2.70737411 100.713 Tmax (h) 1 1 100 Cmax (ppm)12.95494767 22.89919816 176.7603 AUC 0-t 49.29857342 109.8465993 222.819(ppm × h) AUC 0-inf 51.41308527 117.1097277 227.7819 (ppm × h)

Tables 12 and 13: Showing the Mean values±SEM and the PK parametersobtained from the non-compartmental analysis using PKSolver software foreach time point shown in FIG. 19.

When looking at parent compounds specifically (curcumin, DMC and BDMC intheir native form, i.e. unmetabolized), as shown in Table 14 that givesplasma concentration of parent curcuminoids for each time point afterconsumption of 300 mg/kg curcuminoids from standard turmeric extract,turmeric phytosome or the composition as used in the methods/uses of theinvention, the composition as used in the methods/uses of the inventionwas the only one for which we were able to quantify a detectable amountof parent curcuminoids during the first 4 h post-dosing and therefore tocalculate the AUC(0-12 h) and AUC(0-∞) (Table 15). A 10.9-fold increasein Cmax for parent curcuminoids were obtained for the composition asused in the methods/uses of the invention in comparison to the standardturmeric extract.

When looking at parent curcumin specifically (curcumin in its nativeform, i.e. unmetabolized), as shown in Table 16 that gives plasmaconcentration of parent curcumin for each time point after consumptionof 300 mg/kg from standard turmeric extract, turmeric phytosome or thecomposition as used in the methods/uses of the invention, thecomposition as used in the methods/uses of the invention was the onlyone for which we were able to quantify a detectable amount of parentcurcumin during the first 4 h post-dosing and therefore to calculate theAUC(0-12 h) and AUC(0-∞) (Table 16). A 521.8-fold increase in Cmax forparent curcumin was obtained for the composition as used in themethods/uses of the invention in comparison to the standard turmericextract. Moreover, the composition as used in the methods/uses of theinvention induced higher plasmatic level of parent curcumin than theturmeric phytosome formulation (1.8-fold increase in Cmax).

It can be concluded from this first in vivo experiment that thecomposition as used in the methods/uses of the invention with more than6% curcuminoids, obtained with 8.6% turmeric extract, 15.9% sunfloweroil, 2% quillaja extract, and 73.5% modified starch and preparedaccording to Form 1, is able to enhance the bioavailability of totalcurcuminoids and their metabolites but also the bioavailability ofparent compounds in comparison to a standard turmeric extract.

It can be also concluded that the composition as used in themethods/uses of the invention could better improve the bioavailabilityof native curcumin than the turmeric phytosome formulation.

The composition as used in the methods/uses of the invention thereforerepresents an attractive way to enhance parent curcumin bioavailabilitywithout using soy-derived lecithin in the formulation as opposed to theTurmeric phytosome formulation. Also, as curcumin is considered as oneof the most powerful active of turmeric in comparison to DMC and BDMCand their relative reduced, glucuronide or sulfate metabolites (IresonC, Orr S, Jones D J, Verschoyle R, Lim C K, Luo J L, Howells L, PlummerS, Jukes R, Williams M, Steward W P, Gescher A. Characterization ofmetabolites of the chemopreventive agent curcumin in human and rathepatocytes and in the rat in vivo, and evaluation of their ability toinhibit phorbol ester-induced prostaglandin E2 production. Cancer Res.2001 Feb. 1; 61(3):1058-64; Anand P, Thomas S G, Kunnumakkara A B,Sundaram C, Harikumar K B, Sung B, Tharakan S T, Misra K, Priyadarsini IK, Rajasekharan K N, Aggarwal B B. Biological activities of curcumin andits analogues (Congeners) made by man and Mother Nature. BiochemPharmacol. 2008 Dec. 1; 76(11):1590-611; Pal A, Sung B, Bhanu Prasad BA, Schuber P T Jr, Prasad S, Aggarwal B B, Bornmann W G. Curcuminglucuronides: assessing the proliferative activity against human celllines. Bioorg Med Chem. 2014 Jan. 1; 22(1):435-9), the composition asused in the methods/uses of the invention represents a good solution toimprove the biological efficacy of curcumin for different healthconditions like joint health, inflammation, arthritis, atherosclerosis,liver steatosis, liver fibrosis, diabetes, cognition, mild cognitiveimpairment, irritable bowel syndrome.

TABLE 14 concentration of parent curcuminoids (sum of curcumin, DMC andBDMC) for each time point after consumption of 300 mg/kg curcuminoidsfrom standard turmeric extract, turmeric phytosome or the composition asused in the methods/uses of the invention in the first in vivo study.Parent curcuminoids plasmatic levels - Mean ± SEM The composition asused in the methods/uses of the Standard extract Turmeric phytosomeinvention 0.5 h 13.91 ± 10.05 (4/5) 13.91 ± 10.05 (4/5) 151.20 ± 96.93 (5/5)   1 h 0.00 ± 0.00 (0/5) 0.00 ± 0.00 (0/5) 6.95 ± 6.95 (1/5)   2 h0.00 ± 0.00 (0/5) 0.00 ± 0.00 (0/5) 0.30 ± 0.30 (1/5)   4 h 0.00 ± 0.00(0/5) 0.00 ± 0.00 (0/5) 2.55 ± 2.55 (1/5)   6 h 0.00 ± 0.00 (0/5) 0.00 ±0.00 (0/5) 0.00 ± 0.00 (0/5)

The numbers in brackets located next to these values indicate the numberof sample which presented a positive value on the total number ofsamples

TABLE 15 PK parameters obtained from the non-compartmental analysisusing PKSolver software for parent curcuminoids after consumption of 300mg/kg curcuminoids from standard turmeric extract, turmeric phytosome orthe composition as used in the methods/uses of the invention in thefirst in vivo study PK parameters-parent curcuminoids The composition asused in the Standard Turmeric methods/uses of extract phytosome theinvention t½ (h) / / 0.75 Tmax (h) 0.5 0.5 0.5 Cmax (ppb) 13.9 168.3151.2 AUC 0-t (ppb × h) / / 83.8 AUC 0-inf (ppb × h) / / 86.5

TABLE 16 concentration of parent curcumin for each time point afterconsumption of 300 mg/kg curcuminoids from standard turmeric extract,turmeric phytosome or the composition as used in the methods/uses of theinvention in the first in vivo study. Parent curcumin plasmaticlevels-Mean ± SEM the composition as used in the methods/uses of theStandard extract Turmeric phytosome invention 0.5 h 0.20 ± 0.20 (1/5)59.30 ± 35.26 (4/5) 104.37 ± 64.37  (5/5)   1 h 0.00 ± 0.00 (0/5) 0.00 ±0.00 (0/5) 5.83 ± 5.83 (1/5)   2 h 0.00 ± 0.00 (0/5) 0.00 ± 0.00 (0/5)0.30 ± 0.30 (1/5)   4 h 0.00 ± 0.00 (0/5) 0.00 ± 0.00 (0/5) 2.55 ± 2.55(1/5)   6 h 0.00 ± 0.00 (0/5) 0.00 ± 0.00 (0/5) 0.00 ± 0.00 (0/5)

The numbers in brackets located next to these values indicate the numberof sample which presented a positive value on the total number ofsamples

TABLE 17 PK parameters obtained from the non-compartmental analysisusing PKSolver software for parent curcumin after consumption of 300mg/kg curcuminoids from standard turmeric extract, turmeric phytosome orthe composition as used in the methods/uses of the invention in thefirst in vivo study PK parameters-parent curcumin The composition asused in the Standard Turmeric methods/uses of extract phytosome theinvention t½ (h) / / 0.82 Tmax (h) 0.5 0.5 0.5 Cmax (ppb) 0.2 59.3 104.4AUC 0-t (ppb × h) / / 59.6 AUC 0-inf (ppb × h) / / / 62.6

Given the results obtained in the first in vivo study in mice, showingbetter bioavailability of total curcuminoids and parents curcuminoidsand curcumin, we decided to test an optimized formulation with an highercurcuminoids content (12% curcuminoids) prepared according Form 2 with14.4% turmeric extract, 26.8% sunflower oil, 2% quillaja extract, and56.8% modified starch, for its capacity to improve the bioavailabilityof curcuminoids in comparison to a standard turmeric extract in a secondcomparative pharmacokinetic study in mice.

The same methodology (mice housing, acclimatization period, habituationperiod, curcuminoids and their metabolites quantification using LC/MSmethod) was used as described earlier in this Example, but with a highernumber of animals per group and time (n=12/time point/formulation) andblood was sampled at 0.25-, 0.5-, 0.75-, 1 h-, 2 h-, or 8 h-post-dosingin order to specify the kinetic profile during the earliest phase afteroral consumption (300 mg/kg bw) of curcuminoids coming from a standardturmeric extract (with 79.5, 15.0 and 3.0 g/100 g of curcumin, DMC andBDMC respectively and a total of 97.5 g curcuminoids/100 g), a Turmericphytosome formulation (with 18.6, 2.6 and 0.2 g/100 g of curcumin, DMCand BDMC respectively and a total of 21.5 g curcuminoids/100 g) or thecomposition as used in the methods/uses of the invention preparedaccording to Form 2 (with 9.8, 1.6 and 0.2 g/100 g of curcumin, DMC andBDMC respectively and a total of 11.6 g curcuminoids/100 g).

FIG. 20 depicts total curcuminoids and metabolites concentration as afunction of time after consumption of the different formulations (n=72per formulation). The results clearly showed a significant increase ofcurcuminoids and metabolites concentration for the Turmeric phytosomeand the composition as used in the methods/uses of the invention incomparison to the standard turmeric extract. The total curcuminoidsconcentration was higher 0.5 h and 0.75 h after consumption of thecomposition as used in the methods/uses of the invention in comparisonto the Turmeric phytosome formulation, showing surprisingly the betterperformance of the composition as used in the methods/uses of theinvention in comparison to the Turmeric phytosome formulation in termsof improvement of total curcuminoids and metabolites bioavailability.

This was confirmed while calculating the corresponding area under thecurve AUC(0-8 h), AUC(0-∞) and Cmax (FIGS. 21, 22 and 23 respectively)that were 280% higher, 300% higher and 337% higher for the compositionas used in the methods/uses of the invention in comparison to thestandard extract respectively and 6.5% higher, 30% higher and 63% higherfor the composition as used in the methods/uses of the invention incomparison to the Turmeric phytosome formulation respectively (Table18). We also showed that curcuminoids and metabolites from thecomposition as used in the methods/uses of the invention were morerapidly absorbed with a 1.5-fold reduction in Tmax in comparison tostandard extract (0.5 h versus 0.75 h) and a 2-fold reduction in Tmax incomparison to the Turmeric Phytosome formulation (0.5 h versus 1 h)respectively (Table 18). The results also showed surprisingly thatcurcuminoids and metabolites from the composition as used in themethods/uses of the invention were less rapidly excreted with a longerhalf-life (3.8 h versus 2.8 h) in comparison to the Turmeric Phytosomeformulation.

When looking at parent compounds specifically (curcumin, DMC and BDMC intheir native form, i.e. unmetabolized), as shown in Table 19, that givesthe PK parameters of parent curcuminoids after consumption of 300 mg/kgcurcuminoids from standard turmeric extract, Turmeric Phytosome or thecomposition as used in the methods/uses of the invention, thecomposition as used in the methods/uses of the invention wassurprisingly the only one for which we could calculate the AUC(0-8 h)for parent curcumin. A 3.2-fold increase in Cmax for parent curcumin wasobtained for the composition as used in the methods/uses of theinvention in comparison to the standard turmeric extract. No Cmax couldbe calculated for curcumin as no parent curcumin could be found inplasma samples after consumption of the Turmeric phytosome formulation.

It can be concluded from this second in vivo experiment that thecomposition as used in the methods/uses of the invention with a highercurcuminoids content (12% curcuminoids) prepared according to Form 2with 14.4% turmeric extract, 26.8% sunflower oil, 2% quillaja extract,and 56.8% modified starch is unexpectedly able to enhance thebioavailability of total curcuminoids and their metabolites but alsoparent curcumin in comparison to a standard turmeric extract and to theTurmeric phytosome formulation.

The composition as used in the methods/uses of the invention thereforerepresents an attractive way to enhance the bioavailability ofcurcuminoids without using soy-derived lecithin in the formulation asopposed to the Turmeric phytosome formulation.

TABLE 18 PK parameters obtained from the non-compartmental analysisusing PKSolver software for total curcuminoids and metabolites afterconsumption of 300 mg/kg curcuminoids from standard turmeric extract,turmeric phytosome or the composition as used in the methods/uses of theinvention in the second in vivo study PK parameters-parent curcumin Thecomposition as used in the Standard Turmeric methods/uses of the extractphytosome invention t½ (h) 3.98 2.76 3.8 Tmax (h) 0.75 1 0.5 Cmax (ppb)10.83 22.38 36.47 (3.4) [1.6] AUC 0-t (ppbm × h) 31.11 81.74 (2.6) 87.27(2.8) [1.1] AUC 0-inf (ppb × h) 41.56 95.74 (2.3) 124.36 (3.0) [1.3]

The fold increase in AUC or Cmax relative to standard extract is showninto brackets ( ). The fold increase in AUC or Cmax relative to turmericphytosome formulation is shown in square brackets [ ].

TABLE 19 PK parameters obtained from the non-compartmental analysisusing PKSolver software for parent curcuminoids after consumption of300mg/kg curcuminoids from standard turmeric extract, turmeric phytosomeor the composition as used in the methods/uses of the invention in thesecond in vivo study. Standard extract Parent compounds (ppb) Totalparent PK Parameter Unity curcumin DMC BDMC compounds (ppb) t½ h MissingMissing Missing Missing Tmax h 0.25 0.25 0.25 0.25 Cmax ppb 5.55 25.0364.43 114.65 AUC 0-t ppb * h Missing Missing 16.82 29.37 AUC 0-inf_obsppb * h Missing Missing Missing Missing Turmeric Phytosome Parentcompounds (ppb) Total parent PK Parameter Unity curcumin DMC BDMCcompounds (ppb) t½ h Missing Missing Missing Missing Tmax h MissingMissing Missing Missing Cmax ppb Missing Missing Missing Missing AUC 0-tppb * h Missing Missing Missing Missing AUC 0-inf_obs ppb * h MissingMissing Missing Missing The composition as used in the methods/uses ofthe Total parent invention Parent compounds (ppb) compounds PK ParameterUnity curcumin DMC BDMC (ppb) t½ h Missing Missing Missing Missing Tmaxh 0.25 0.25 0.25 0.25 Cmax ppb 17.94 11.13 6.34 60.45 AUC 0-t ppb * h10.8778375 Missing Missing 32.13 AUC 0-inf_obs ppb * h Missing MissingMissing Missing

Example 7—A Comparative Pharmacokinetic Study in Healthy Volunteers toEvaluate the Ability of a Composition of the Invention to Enhance theBioavailability of Curcuminoids

This study had two objectives:

1. Primary Objective

To assess plasmatic concentrations profile of total curcuminoids(curcumin, demethoxycurcumin (DMC), bisdemethoxycurcumin (DBMC) andtheir metabolites) on a 24 hours period after consumption of a singledose of 300 mg of composition of the invention (Turmipure GOLD™ 30%curcuminoids formulation) compared to 1500 mg Standard turmeric powderextract 95% curcuminoids.

2. Secondary Objectives

To assess, plasmatic concentrations profiles of the followingparameters, after consumption of a single dose of five studied productscontaining either 1425 mg (standard turmeric powder extract 95%curcumindoids, Curcumin C3 complex California Gold Nutrition), 200 mg(Curcuma Platinum MannaVital), 90 mg (of a composition of the invention(Turmipure GOLD™ 30% curcuminoids)) or 60 mg (Curcumin Cell'Innov) ofactive substance:

-   -   Total curcuminoids;    -   Parent compounds (curcumin, DMC, BDMC) and their metabolites:        curcumin, glucuronide and sulfate; DMC glucuronide and sulfate;        BDMC glucuronide and sulfate; tetrahydrocurcumin (THC) native,        glucuronide and sulfate; hexahydrocurcumin (HHC) native,        glucuronide and sulfate.

The study was a monocentric, randomized, cross-over and open clinicaltrial.

The study commenced with a screening/inclusion visit (V0) followed by 5experimental sessions (V1 to V5) during which the studied products wereconsumed by subjects (one different product at each session for eachrandomized subject). The V1 visit, took place a maximum of 3 weeks afterV0, and can also constitute the randomization visit.

Each experimental session (V1 to V5) was separated by 1 week minimum and2 weeks maximum. During each experimental session, subjects underwentkinetic blood sampling during 8 hour periods. The last kinetic bloodsample was taken the day after each experimental session, 24 hours afterthe beginning of the kinetic. Urine collection was also performed duringthese visits for biobanking.

The subjects first urination was collected the morning of eachexperimental visit (totality of this first urination), with additionalcollections at 0 to 8 hours during the kinetic blood sampling on siteand 8 to 24 hours when they came home. The last urine collection wasbrought back the day after the experimental visit (when they came backfor the last blood sample, T24H, of the kinetic blood sampling).

Standard meals were provided to volunteers for diner before eachexperimental session and during the all duration of each kinetic(breakfast, lunch and afternoon collation).

The end of study was the day after the last experimental session V5(V5-24H).

-   -   30 subjects were recruited for this study, according to the        following main inclusion and exclusion criteria:        -   I1: Age between 18 and 45 years (limits included);        -   I2: BMI between 19 and 25 kg/m² (limits included);        -   I3: Weight stable, within ±3 kg in the last three months;        -   I4: With routine blood chemistry values within the normal            range;        -   I5: For women: Non-menopausal with the same reliable            contraception since at least 3 cycles before the beginning            of the study and agreeing to keep it during the entire            duration of the study (condom with spermicidal gel and            estrogen/progestin combination contraception accepted) or            menopausal without or with hormone replacement therapy            (estrogenic replacement therapy begun from less than 3            months excluded);        -   I6: Non-smoking or with tobacco consumption≤5 cigarettes/day            and agreeing not to smoke during all experimental session            (V1 to V5);        -   I7: Agreeing not to consume food, drink and condiment            containing curcumin, or other curcuminoids (DMC, BDMC)            during the all duration of the study;        -   I8: Good general and mental health with in the opinion of            the investigator: no clinically significant and relevant            abnormalities of medical history or physical examination;        -   E1: Suffering from a metabolic or endocrine disorder such as            diabetes, uncontrolled or controlled thyroidal trouble or            other metabolic disorder;        -   E2: Suffering from a severe chronic disease (e.g. cancer,            HIV, renal failure, ongoing hepatic or biliary disorders,            chronic inflammatory digestive disease, arthritis or other            chronic respiratory trouble, etc.) or gastrointestinal            disorders found to be inconsistent with the conduct of the            study by the investigator (e.g. celiac disease);        -   E3: Suffering from liver diseases;        -   E4: Current disease states that are contraindicated to            subjects with dietary supplementation: chronic diarrhea,            constipation or abdominal pain, Inflammatory bowel diseases            (Crohn's disease or ulcerative colitis), Cirrhosis, chronic            laxatives use . . . ;        -   E5: Suffering from Irritable Bowel Syndrome (IBS) diagnosed            by a medical doctor and treated with chronic medication;        -   E6: Having medical history of current pathology which could            affect the study results or expose the subject to an            additional risk according to the investigator;        -   E7: Recent gastroenteritis or food borne illness such as            confirmed food poisoning (less than 1 month);        -   E8: Who made a blood donation in the 3 months before the V0            visit or intending to make it within 3 months ahead;        -   E9: With a low venous capital not allowing to perform            kinetic of blood samples according to the investigator's            opinion;        -   E10: With a known or suspected food allergy or intolerance            or hypersensitivity to any of the study products' ingredient            and/or of the standard meals (gluten intolerance, celiac            disease, etc.);        -   E11: Pregnant or lactating women or intending to become            pregnant within 3 months ahead;        -   E12: Exhibiting alcohol or drug dependence;        -   E13: On any chronic drug treatment (for example            anticoagulant, antihypertensive treatment, treatment            thyroid, asthma treatment, anxiolytic, antidepressant,            lipid-lowering treatment, corticosteroids, phlebotonic,            veino-tonic, drug with impact on blood circulation . . . )            excepting oral and local contraceptives;        -   E14: Currently taking (and during the past 3 months) any            supplementation from botanical origins;        -   E15: Having consumed curcumin-containing food supplements            (curcumin, turmeric and curry) or foods (curcumin, turmeric,            E100, and curry) defined as at least 3 times per week and            for 2 weeks prior to testing;        -   E27: Control record (glycaemia, GGT, ASAT, ALAT, urea,            creatinine and complete blood count) with clinically            significant abnormality according to the investigator.

Five products, which are dietary supplements in shape of capsules, weretested as part of this study:

-   -   1. Standard Turmeric powder extract 95% curcuminoids 1500 mg        consumed as capsules (4 capsules; 375 mg powder per capsule)        (STE),    -   2. C3 Complex® 95% curcuminoids (1500 mg)+BioPerine® 95%        piperine (15 mg) consumed as commercial product Curcumin C3        complex California Gold Nutrition (3 caps; 500 mg C3 complex        powder+5 mg bioperine powder per capsule) (TEP),    -   3. Meriva® (1000 mg) consumed as commercial product Curcuma        Platinum Mannavital 20% curcuminoids (2 caps; 500 mg powder per        capsule) (PHYT),    -   4. Novasol® (1000 mg) consumed as commercial product Curcumin        Cell innov 6% curcuminoids (2 caps; 500 mg liquid per capsule)        (NOV),    -   5. A composition as defined herein comprising turmeric extract,        sunflower oil, quillaja extract, and arabic gum, consumed as        capsule (1 capsule; 300 mg powder per capsule) (TURMIPURE GOLD).

In order to ensure the healthy status of subjects and to checkeligibility criteria, a blood sample was taken during V0 visit forcontrol record analysis and pregnancy test for non-menopausal women(βhCG dosage).

The sample was taken after a physical examination and verification ofeligibility criteria. A maximum of 10 mL was collected.

Measurement of blood pressure were performed at each visit during thephysical examination with an electronic blood pressure monitor(Carescape Dinamap®V100). Heart Rate (HR, in bpm), Systolic BloodPressure (SBP, in mmHg) and Diastolic Blood Pressure (DBP, in mmHg) werealso assessed.

All subjects attended in a 12-hour fasted state.

In preparation for the V1 to V5 visits, after the clinical examination,a venous catheter was placed on elbow crease of the subject. Thiscatheter allowed blood sampling for the kinetic without any additionalpricks.

Kinetic sample lasted approximately 8 hours, with all the subjectsstaying at the clinical investigational center. Ten (10) blood samplingwere taken according to the following schedule:

-   -   T-10 (baseline),    -   T15>T30>T45>T60>T90>T120>T240>T360>T480,

A margin of ±30 s was authorized for T15, 1 min for T30 and T45, 2 minfor T60 and T90, ±5 min for T120 to T480.

The T0 time point corresponds to study product consumption.

The volunteer was allowed to consume his/her standard lunch about 4hours after study product consumption (just after at T240 time-point)and standard afternoon meal about 8 hours after study productconsumption. Lunch was consumed in 30 minutes maximum. Water was notpermitted 1 h before and 1 h after product administration. The catheterwas removed after the last time point, T480.

The volunteers were then asked to come again at the clinicalinvestigational site, in a 12-hour fasting state, the day after thevisit for the last blood sampling of the kinetic, T24H. Classic venousblood sample material was used (single prick). The biological parameterswere assessed with these samplings being analyzed in plasma; thus onlyEDTA tubes were used (5 mL per sampling).

A calibration curve was prepared in the range 10-600 ng/mL for each 5curcuminoids (Phytolab, Vestenbergsgreuth, Germany) adding 50 ppb oflabelled curcumins (TLC pharmachem, Ontario, Canada) as an internalstandard to ensure retention time stability and instrument correctionvariation. Acetonitrile was used as the diluent for each solution. Forfree curcuminoid determination, exactly 500 μL of coldmethanol:aetonitrile (15:85) mixture containing internal standardssolution (50 ng/mL) was loaded over 100 μL of plasma sample into Captiva96 wells plate (EMR lipids from Agilent, see FIG. 18). After mixing andfiltration the curcumins was eluted with cold water:acetonitrile (1:4)mixture and the eluate was injected into LC/MS system. Captiva EMR Lipidplates were designed to effectively remove phospholipids from plasma.For the determination of total conjugated curcuminoid metabolites(glucuronide and sulfate metabolites), 60 μL of plasma sample was mixedwith 60 μL of enzyme solution (either glucuronidase at 1 mg/mL, 100 mMphosphate buffer pH 6.8 or sulfatase 10 mg/mL, 100 mM acetate buffer, pH5.0) for 1 hours at 37° C. with constant agitation (Eppendorf,Thermomixer C, 400 rpm). After this hydrolysis step, the protocol wasthe same as for free curcuminoids using Captiva 96 wells plate EMRlipid.

EMR-Lipid protocol for the human plasma treatment before injection is asdepicted below.

The LC/MS conditions were as follows. The autosampler (5° C.) and LCsystem was an Agilent Infinity II 1290 integrated system. Agilent 6420Triple quadrupole mass spectrometer was used during the study, withelectrospray ionization. The metabolites were eluted from the BEH C18column (100×2.1 mm, 1.7 μm; Waters) with a mobile phase consisting of0.1% formic acid in water in HPLC grade (solvent A) and 0.1% formic acidin acetonitrile (solvent B), at a flow rate of 0.4 mL/min and a columntemperature of 35° C. The elution was in gradient from 40-60% B at 0-3min. The injection volume was 2 μL for standard and samples. For eachreference compound, a relevant transition of the precursor-to-productions was detected with the utilization of the multiple reactionmonitoring (MRM) mode. Each of the 5 analytes was determined in MS1 fullscan tests and the product ions in MS/MS experiments. MRM transitions ofeach analyte was optimized using direct infusion and Optimizer B.08.00workstation software solution (Agilent technologies, Santa Clara,Calif., USA). See Table 20 for the optimal selected conditions. The massspectrometer parameters was set as follows: ESI source both in negativeand positive mode; drying gas (N2) flow rate, 10 L/min; gas temperature,350° C.; nebulizer, 40 psi; and capillary, 4.0 kV. The MS system wasfully calibrated prior to running according to manufacturer'sguidelines. Data analysis was carried out on Agilent MassHunterQuantitative/Qualitative analysis B.07.00 (Agilent technologies, SantaClara, Calif., USA).

TABLE 20 Retention times (Tr), multiple reaction monitoring (MRM)transitions, and optimized tandem mass spectrometry (MS/MS) detectionparameters of 5 curcuminoids and internal standard. Prec. Prod. Ion Q1ions Q3 Dwell Mass Mass time Frag Cpd Name Rt (min) ISTD ? (Da) (Da)(ms) (V) CE (V) Polarity Curcumin d6 3.05 Yes 375.2 180.0 50 65 24Positive 177.0 50 120 20 Positive Curcumin 3.05 No 369.1 145.0 50 120 36Positive 117.0 50 120 48 Positive DMC d7 2.89 Yes 346.1 151.0 50 105 32Positive DMC 2.89 No 339.1 177.0 50 105 20 Positive 147.0 50 105 28Positive 91.1 50 105 60 Positive BDMC d8 2.74 Yes 317.1 151.0 50 80 24Positive BDMC 2.74 No 309.1 147.0 50 95 24 Positive 119.0 50 95 40Positive 91.1 50 95 60 Positive HHC d6 1.34 Yes 379.2 182.1 50 110 20Negative HHC 1.34 No 373.1 193.1 50 100 12 Negative 179.1 50 100 16Negative 121.0 50 100 56 Negative THC d6 2.84 Yes 377.1 135.1 50 105 60Negative THC 2.84 No 371.1 235.1 50 120 12 Negative 193.1 50 120 20Negative 135.0 50 120 56 Negative

Analysis Population

-   -   ITT population: All subjects randomized in the study having        consumed at least one dose of the products (n=30)    -   PP population: Subjects included in the ITT population who        completed the study presenting no major protocol deviations        (n=30). The following subjects were excluded from the PP        population:        -   Subject SN01-040-V5 for all parameters    -   SAFETY population: All subjects randomized in the study having        consumed at least one dose of the products (n=30)

TABLE 21 Description of the study population at baseline showing meanand standard deviation. Included subjects Number of subjects (N = 30)Women/Men 16 (53.3)/14 (46.7) Age (years) 33.6 (6.79) Weight (kg) (V0)64.5 (11.09) BMI (kg/m²) (V0) 22.1 (2.13)

Software Environment

-   -   Statistical analyses were performed by Biofortis using SAS®        software version 9.3 (SAS Institute Inc., Cary, N.C., USA).    -   Significance level    -   For all statistical tests (two-tailed), the 0.05 level of        significance was used to justify a claim of a statistically        significant effect.    -   Methods of handling missing data for kinetics    -   If more than 2 values or 2 consecutive values are missing in the        kinetics, the AUC calculation cannot be performed and the        kinetics were considered as missing in the statistical analyses        (no missing data replacement was performed);    -   If a data is missing at T-10 time-point, the AUC calculation        cannot be performed and the kinetics were considered as missing        in the statistical analyses (no missing data replacement was        performed);    -   If a value (except the baseline value and the value at the last        time-point) is missing in the kinetics, it was replaced by the        value obtained using the CopyMean method developed by Genolini        (Genolini, 2013);    -   If a value at the last time-point (T1440=T24 h) of the kinetics        is missing, no missing data replacement was performed.    -   In case of non-complete kinetics after missing data handling,        the AUC cannot be calculated.

→This method was applied on ITT and PP populations.

Derived Variables

-   -   Total curcuminoids=Curcumin+DMC+BDMC+THC+HHC+Curcumin        glucuronide+DMC glucuronide+BDMC glucuronide+THC glucuronide+HHC        glucuronide+Curcumin sulfate+DMC sulfate+BDMC sulfate+THC        sulfate+HHC sulfate

If all of these 15 elements are missing, total curcuminoids cannot becalculated. If at least one of these 15 elements is quantified, totalcurcuminoids were calculated.

-   -   Total Parent compounds=sum of curcumin+DMC+BDMC    -   Total Parent compounds and their relative sulfate and        glucuronide metabolites=Curcumin+Curcumin glucuronide+Curcumin        sulfate+DMC+DMC glucuronide+DMC sulfate+BDMC+BDMC        glucuronide+BDMC sulfate    -   Curcumin and its relative sulfate and glucuronide        metabolites=Curcumin+Curcumin glucuronide+Curcumin sulfate    -   DMC and its relative sulfate and glucuronide metabolites=DMC+DMC        glucuronide+DMC sulfate    -   BDMC and its relative sulfate and glucuronide        metabolites=BDMC+BDMC glucuronide+BDMC sulfate    -   Curcumin and all its relative metabolites=Curcumin+Curcumin        glucuronide+Curcumin sulfate+THC+THC glucuronide+THC        sulfate+HHC+HHC glucuronide+HHC sulfate    -   Relative bioavailability between 0 to 24 hours=Ratio of the        dose-normalized AUC0-24 h for the different tested formulation        to the dose-normalized AUC0-24 h obtained for the reference        product (turmeric extract 95% curcuminoids)    -   Relative bioavailability between 0 to 8 hours=Ratio of the        dose-normalized AUC0-8 h for the different tested formulation to        the dose-normalized AUC0-8 h obtained for the reference product        (turmeric extract 95% curcuminoids)    -   Relative bioavailability between 0 to infinity=Ratio of the        dose-normalized AUC0-∞ for the different tested formulation to        the dose-normalized AUC0-∞ obtained for the reference product        (turmeric extract 95% curcuminoids)

Data Handling of Values Below the Limit of Detection (LOD)

-   -   Some values below the limit of detection (LOD) were identified        for curcumin (native, glucuronide and sulfate) expressed as        <<0.62>> in the database.

→The number and percentage of values under the LOD were given for eachparameter and visit.

Production of Graphical Representations

-   -   Quantitative variable on observed means: Box-and-whiskers plots        for AUC parameters (illustrated in Figure below)

Checking of Statistical Tests Assumptions

-   -   Assumptions of normality and homoscedasticity were investigated        by graphical representations of residuals produced by        statistical models. In case of strong deviation from normality        and/or homoscedasticity, log transformation (log 10) of study        endpoints was considered.

Note for production of results:

-   -   STE=Standard turmeric powder extract 95% curcuminoids 1500 mg    -   TEP=Curcumin C3 complex California Gold Nutrition (1500 mg C3        Complex®)    -   NOV=Curcumin Cell'Innov (1000 mg Novasol®)    -   PHYT=Curcuma Platinum MannaVital (1000 mg Meriva®)    -   Turmipure GOLD™=Turmipure Gold 30% curcuminoids 300 mg

Statistical Methodology

-   -   Primary endpoint: Dose-normalized AUC between 0 and 24 hours was        analyzed using the following mixed model for repeated        measurements (SAS® PROC MIXED, statistical model n° 1):

Y=Product+Visit+Baseline+Subject_(random)

with:

-   -   Y: Dose-normalized AUC between 0 and 24 hours of analyt        plasmatic concentration;    -   Product: Turmipure Gold™, STE, TEP, NOV, PHYT;    -   Visit: Visit V1 to V5;    -   Baseline: Parameter's value at T-10 time-point (T0 for AUC        calculation);    -   Subject_(random): Random factor.    -   If significant Visit effect (p<0.05): secondary analysis        realized on first period (visit) in order to assess the product        effect.    -   Comparison between products of interest→Turmipure Gold™ compared        to STE

Additional Analysis: Investigation of Gender Effect

-   -   Gender effect was investigated in this study using the following        mixed model for repeated measurements (SAS® PROC MIXED,        statistical model n° 2):

Y=Product+Visit+Gender+Product*Gender+Baseline+Subject_(random)

With:

-   -   Y: Endpoint;    -   Product: Turmipure Gold™, STE, TEP, NOV, PHYT;    -   Visit: Visit V1 to V5;    -   Gender: Female or Male;    -   Product*Gender: interaction between the product and the gender;    -   Baseline: Parameter's value at T-10 time-point (T0 for AUC        calculation);    -   Subject_(random): Random factor.    -   Comparisons between products of interest;    -   Turmipure GOLD™ compared to STE;    -   TEP compared to STE;    -   NOV compared to STE;    -   PHYT compared to STE;    -   TEP compared to Turmipure GOLD™;    -   NOV compared to Turmipure GOLD™;    -   PHYT compared to Turmipure GOLD™    -   If significant Visit effect (p<0.05): secondary analysis        realized on first period (visit) in order to assess the product        effect.    -   If significant Product*Gender interaction effect (p<0.05):        treatment effect investigated in men and women separately (with        production of descriptive statistics and graphic        representations)    -   If significant Product*Gender interaction effect (p>0.05):        treatment effect investigated globally (women and men together)

Statistical Methodology for Secondary Endpoints (Except for RelativeBioavailability)

-   -   Secondary endpoints were analyzed using the following mixed        model for repeated measurements (SAS® PROC MIXED, statistical        model n° 1):

Y=Product+Visit+Baseline+Subject_(random)

-   -   If significant Visit effect (p<0.05): secondary analysis        realized on first period (visit) in order to assess the product        effect.    -   Comparison between products of interest:    -   Turmipure GOLD™ compared to STE;    -   TEP compared to STE;    -   NOV compared to STE;    -   PHYT compared to STE;    -   TEP compared to Turmipure GOLD™;    -   NOV compared to Turmipure GOLD™;    -   PHYT compared to Turmipure GOLD™    -   Statistical methodology for relative bioavailability    -   Secondary endpoints were analyzed using the following mixed        model for repeated measurements (SAS® PROC MIXED, statistical        model n° 1):

Y=Product+Visit+Subject_(random)

-   -   If significant Visit effect (p<0.05): secondary analysis        realized on first period (visit) in order to assess the product        effect.    -   Comparison between products of interest:    -   TEP compared to Turmipure GOLD™;    -   NOV compared to Turmipure GOLD™;    -   PHYT compared to Turmipure GOLD™

Summary of the Results of the Primary Endpoints

Table 22 and 23: Initial Analysis of ITT and PP Populations

ITT population Between-group analysis Product effect- Comparison betweenStatistical Endpoint Statistical significance Products significanceDose-normalized of

Turmipure GOLD ™ vs STE

Turmipure > STE AUC_(0-24h) of Total (primary endpoint) curcuminoids TEPvs STE

(log-transformed data) NOV vs STE

NOV > STE PHYT vs STE

PHYT > STE TEP vs Turmipure GOLD ™

TEP < Turmipure NOV vs Turmipure GOLD ™

NOV > Turmipure PHYT vs Turmipure GOLD ™

PHYT < Turmipure

PP population Between-group analysis Product effect- Comparison betweenStatistical Endpoint Statistical significance Products significanceDose-normalized of

Turmipure GOLD ™ vs STE

Turmipure > STE AUC_(0-24h) of Total (primary endpoint) curcuminoids TEPvs STE

(log-transformed data) NOV vs STE

NOV > STE PHYT vs STE

PHYT > STE TEP vs Turmipure GOLD ™

TEP < Turmipure NOV vs Turmipure GOLD ™

NOV > Turmipure PHYT vs Turmipure GOLD ™

PHYT < Turmipure

Table 24 and 25: Additional Analysis of ITT and PP Populations(Investigation of Gender Effect)

ITT population Between-group analysis Product*Gender effect- Comparisonbetween Statistical Endpoint Statistical significance Productssignificance Dose-normalized of

Turmipure GOLD ™ vs STE

Turmipure > STE AUC_(0-24h) of Total (primary endpoint) curcuminoids TEPvs STE

(log-transformed data) NOV vs STE

NOV > STE PHYT vs STE

PHYT > STE TEP vs Turmipure GOLD ™

TEP <Turmipure NOV vs Turmipure GOLD ™

NOV >Turmipure PHYT vs Turmipure GOLD ™

PHYT <Turmipure

PP population Between-group analysis Product*Gender effect- Comparisonbetween Statistical Endpoint Statistical significance Productssignificance Dose-normalized of

Turmipure GOLD ™ vs STE

Turmipure > STE AUC_(0-24h) of Total (primary endpoint) curcuminoids TEPvs STE

(log-transformed data) NOV vs STE

NOV > STE PHYT vs STE

PHYT > STE TEP vs Turmipure GOLD ™

TEP <Turmipure NOV vs Turmipure GOLD ™

NOV >Turmipure PHYT vs Turmipure GOLD ™

PHYT <Turmipure

p-value < 0.05 (statistically signifcant);

p-value > 0.05 (statistically non-significant

TABLE 26 Dose-normalized of AUC_(0-24h) of Total curcuminoids TurmipureSTE product TEP productNOV productPHYT product GOLD ™ product VariableStatistics (n = 30) (n = 30) (n = 30) (n = 30) (n = 30) Dose-normalizedN 30 30 30 29 30 AUC_(0-24H) of Total N Miss 0 0 0 1 0 curcuminoids Mean(SD) 3.7 (1.75) 3.2 (1.69) 136.1 (37.40) 13.0 (9.65) 72.9 (25.49) (ng ·h/mL/mg) (Min; Max) (0.7; 9.7) (0.8; 8.7) (69.8; 220.8) (1.7; 42.0)(16.4; 139.6) Median (Q1; Q3) 3.7 (2.5; 4.3) 3.0 (2.1; 4.1) 141.8(105.6; 10.7 (6.2; 17.0) 69.7 (55.2; 87.8) 157.8)

From the above analysis, it was concluded that for the ITT population:

Between-Group Analysis (all Genders Taken Together)

-   -   No significant visit is identified (p=0.2245)→Consequently, the        analysis was performed on all visits.    -   Significant Product effect (p<0.0001):        -   Primary endpoint: There is a statistically significant            difference between Turmipure GOLD™ and STE (adjusted            p<0.0001; diff[adjusted CI95%]=1.32 [1.18; 1.46]).        -   Others comparisons:            -   TEP vs STE (adjusted p=0.6948)            -   NOV vs STE (adjusted p<0.0001; diff[adjusted CI95%]=1.62                [1.48; 1.76])→NOV>STE            -   PHYT vs STE (adjusted p<0.0001; diff[adjusted                CI95%]=0.48 [0.34; 0.62])→PHYT>STE            -   TEP vs Turmipure GOLD™ (adjusted p<0.0001; diff[adjusted                CI95%]=−1.39 [−1.53;−1.25])→TEP<Turmipure GOLD™            -   NOV vs Turmipure GOLD™ (adjusted p<0.0001; diff[adjusted                CI95%]=0.29 [0.15; 0.43])→NOV>Turmipure GOLD™            -   PHYT vs Turmipure GOLD™ (adjusted p<0.0001;                diff[adjusted CI95%]=−0.84 [−0.99;−0.70])→PHYT<Turmipure                GOLD™    -   Additional analysis: Investigation of Gender effect        -   No significant Visit (p=0.2456) and Product*Gender            interaction (p=0.3804) effects: Analysis performed all            gender taken together and on all visits.        -   Significant Product effect (p<0.0001):            -   TEP vs STE (adjusted p=0.7091)            -   NOV vs STE (adjusted p<0.0001; diff[adjusted CI95%]=1.61                [1.47; 1.75])→NOV>STE            -   PHYT vs STE (adjusted p<0.0001; diff[adjusted                CI95%]=0.48 [0.34; 0.62])→PHYT>STE            -   Turmipure GOLD™ vS STE (adjusted p<0.0001; diff[adjusted                CI95%]=1.32 [1.18; 1.46])+Turmipure GOLD™>STE            -   TEP vs Turmipure GOLD™ (adjusted p<0.0001; diff[adjusted                CI95%]=−1.39 [−1.52;−1.25])→TEP<Turmipure GOLD™            -   NOV vs Turmipure GOLD™ (adjusted p<0.0001; diff[adjusted                CI95%]=0.29 [0.15; 0.43])→NOV>Turmipure GOLD™            -   PHYT vs Turmipure GOLD™ (adjusted p<0.0001;                diff[adjusted CI95%]=−0.84 [−0.98;−0.70])→PHYT<Turmipure                GOLD™

For the PP population:

-   -   Between-group analysis (all genders taken together)        -   Results are similar to results observed on ITT population.        -   Additional analysis: Investigation of Gender effect        -   Results are similar to results observed on ITT population.

Summary of the Results of the Secondary Endpoints

The results of the secondary endpoints are shown in the tables below forboth the ITT (Tables 27 to 43) and PP (Tables 44 to 60) Populationsrespectively. The graphical representation of the data is provided inFIGS. 24 to 37.

The following key applies to each table, indicating the statisticalsignificance of each result.

p-value < 0.05 (statistically significant);

p-value ≥ 0.10 (statistically non significant); *Analysis performed onV1 visit only (n = 30)

TABLE 27 Analysis of total curcuminoids (ng/mL) between products in theITT population. Between-group analysis-Satisfied significance ofcomparisons between products (adjusted p-value, Tokey adjustment)Termipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP NOV PHYTTurmipure Turmipure Turmipure Endpoint effect effect vs STE vs STE vsSTE vs STE GOLD ™ GOLD ™ GOLD ™ DN of AUC0-24h

(ng · h/mL/mg) [Log10] Turmipure > STE STE STE Turmipure TurmipureTurmipure AUC0-24h [ng · h/mL]

[Log10]

STE STE Turmipure Turmipure Turmipure DN of AUC0-8h

Turmipure > STE

(ng · h/mL/mg) STE STE Turmipure Turmipure Turmipure [Log10]

AUC0-8h

(ng · h/mL) Turmipure > STE STE STE Turmipure Turmipure Turmipure[Log10] DN of AUCa-infinity

(ng · h/mL/mg) Turmipure > STE STE Turmipure Turmipure [Log10]AUC0-infinity

(ng · h/mL) [Log10] Normalized Cmax

(ng · h/mL/mg) Turmipure > STE STE STE Turmipure Turmipure Turmipure[Log10] Cmax

(ng · h/mL) Turmipure > STE STE STE Turmipure Turmipure Turmipure[Log10] Ret. bio. between 0 and

24 h Turmipure Turmipure Turmipure [Log10] Ret. bio. between 0 and

8 h Turmipure Turmipure Turmipure [Log10] Ret. bio. between 0 and

infinity

[Log10] Half-life (minutes)

[Log10] Turmipure > STE STE Turmipure Turmipure Terminal elimination

rate constant Turmipure > STE STE Turmipure

Turmipure [Log10] Tmax minutes

[Log10] STE STE Turmipure Turmipure

indicates data missing or illegible when filed

TABLE 28 Analysis of total curcumin (ng/mL) between products in the ITTpopulation. Between-group analysis-Satisfied significance of comparisonsbetween products (adjusted p-value, Tokey adjustment) Termipure TEP vsNOV vs PHYT vs Visit Product GOLD ™ TEP NOV PHYT Turmipure TurmipureTurmipure Endpoint effect effect vs STE vs STE vs STE vs STE GOLD ™GOLD ™ GOLD ™ DN of AUC0-24h

(ng · h/mL/mg) [Log10] Turmipure > STE Turmipure AUC0-24h [ng · h/mL]

[Log10] DN of AUC0-8h

(ng · h/mL/mg) [Log10] AUC0-8h

(ng · h/mL) [Log10] DN of AUCa-infinity

(ng · h/mL/mg) Turmipure > STE Turmipure [Log10] AUC0-infinity

(ng · h/mL) [Log10] Normalized Cmax

(ng · h/mL/mg) [Log10] Cmax

(ng · h/mL) [Log10] Ret. bio. between 0 and

24 h [Log10] Ret. bio. between 0 and

8 h Turmipure [Log10] Ret. bio. between 0 and

infinity [Log10] Half-life (minutes)

[Log10] Terminal elimination

rate constant [Log10] Tmax minutes

[Log10]

indicates data missing or illegible when filed

TABLE 29 Analysis of total curcumin (ng/mL) between products in the ITTpopulation. Between-group analysis-Satisfied significance of comparisonsbetween products (adjusted p-value, Tokey adjustment) Termipure TEP vsNOV vs PHYT vs Visit Product GOLD ™ TEP NOV PHYT Turmipure TurmipureTurmipure Endpoint effect effect vs STE vs STE vs STE vs STE GOLD ™GOLD ™ GOLD ™ DN of AUC0-24h

(ng · h/mL/mg) [Log10] Turmipure > STE STE STE Turmipure TurmipureTurmipure AUC0-24h [ng · h/mL]

[Log10] STE STE Turmipure Turmipure DN of AUC0-8h

(ng · h/mL/mg) Turmipure > STE STE STE Turmipure Turmipure Turmipure[Log10] AUC0-8h

(ng · h/mL) STE STE Turmipure Turmipure [Log10] DN of AUCa-infinity

(ng · h/mL/mg) Turmipure > STE STE STE Turmipure Turmipure [Log10]AUC0-infinity

(ng · h/mL) Turmipure [Log10] Normalized Cmax

(ng · h/mL/mg) Turmipure > STE STE STE Turmipure Turmipure Turmipure[Log10] Cmax

(ng · h/mL) STE STE Turmipure Turmipure [Log10] Ret. bio. between 0 and

24 h Turmipure Turmipure Turmipure [Log10] Ret. bio. between 0 and

8 h Turmipure Turmipure Turmipure [Log10] Ret. bio. between 0 and

infinity Turmipure Turmipure [Log10] Half-life (minutes)

[Log10] Turmipure < STE STE Terminal elimination

rate constant Turmipure > STE STE [Log10] Tmax minutes

[Log10] STE Turmipure

indicates data missing or illegible when filed

TABLE 30 Analysis of curcumin sulfate (ng/mL) between products in theITT population. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment) VisitProduct Turmipure TEP vs Turmipure NOV vs Turmipure PHYT vs TurmipureEndpoint effect effect GOLD ™ vs STE TEP vs STE NOV vs STE PHYT vs STEGOLD ™ GOLD ™ GOLD ™ DN of AUC0-24 h p = 0.0037* p < 0.0001 p < 0.0001; 

  p < 0.0001; NOV > p < 0.0001; PHYT > p < 0.0001; TEP <  

  p = 0.0017; PHYT < (ng · h/mL/mg) Turmipure > STE STE STE TurmipureTurmipure [Log10] AUC0-24 h p = 0.0037*  

   

   

   

   

   

   

   

  (ng · h/mL) [Log10] DN of AUC0-8 h p = 0.0 

 * p < 0.0001 p < 0.0001;  

  p < 0.0001; NOV > p < 0.0001; PHYT > p < 0.0001; TEP < p = 0.0041;NOV > p < 0.0001; PHYT < (ng · h/mL/mg) Turmipure > STE STE STETurmipure Turmipure Turmipure [Log10] AUC0-8 h (ng · h/mL) [Log10] p =0.0293* p = 0.00 

   

   

   

   

   

   

   

  DN of AUC0-infinity  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; NOV > p < 0.0001; PHYT > p < 0.0001; TEP <  

  p < 0.0001; PHYT < (ng · h/mL/mg) [Log10] Turmipure > STE STE STETurmipure Turmipure AUC0-infinity  

   

   

   

   

   

   

   

   

  (ng · h/mL) [Log10] Normalized Cmax p = 0.0003* p < 0.0001 p < 0.0001; 

  p < 0.0001; NOV > p < 0.0001; PHYT > p < 0.0001; TEP < p < 0.0001;NOV > p = 0.0005; PHYT < (ng/mL/mg) [Log10] Turmipure > STE STE STETurmipure Turmipure Turmipure Cmax (ng/mL) p = 0.0003* p < 0.0001  

   

  p = 0.0 

 ; NOV >  

   

  p = 0.002 

 ; NOV >  

  [Log10] STE Turmipure Rel. bio. between 0 and 24 h p = 0.0260* p <0.0001  

   

   

   

  p < 0.0001; TEP <  

  p = 0.0015; PHYT < [Log10] Turmipure Turmipure Rel. bio. between 0 and8 h  

  p < 0.0001  

   

   

   

  p < 0.0001; TEP < p = 0.0002; NOV > p < 0.0001; PHYT < [Log10]Turmipure Turmipure Turmipure Rel. bio. between 0 and p = 0.0100* p =0.0143  

   

   

   

   

   

   

  infinity [Log10] Half-life (minutes)  

   

   

   

   

   

   

   

   

  [Log10] Terminal elimination  

   

   

   

   

   

   

   

   

  rate constant [Log10] Tmax (minutes)  

  p < 0.0001  

   

  p < 0.0001; NOV <  

  p = 0.0 

 95; TEP > p < 0.0001, NOV < p = 0.0043; PHYT > [Log10] STE TurmipureTurmipure Turmipure

indicates data missing or illegible when filed

TABLE 31 Analysis of curcumin and its relative sulfate and glucuronidemetabolites (ng/mL) between products in the ITT population.Between-group analysis-Statistical significance of comparisons betweenproducts (adjusted p-value, Tukey adjustment) Turmipure TEP vs NOV vsPHYT vs Visit Product GOLD ™ TEP NOV Turmipure Turmipure TurmipureEndpoint effect effect vs STE vs STE vs STE PHYT vs STE GOLD ™ GOLD ™GOLD ™ DN of  

  p < p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; PHYT <AUC0-24 h 0.0001 Turmipure > NOV > STE PHYT > STE TEP < NOV > Turmipure(ng · h/mL/mg) STE Turmipure Turmipure [Log10] AUC0-24 h  

  p <  

   

  p = 0.0173; p < 0.0001;  

  p = 0.0031; p < 0.0001; PHYT < (ng · h/mL) 0.0001 NOV > STE PHYT > STENOV > Turmipure [Log10] Turmipure DN of AUC0-8 h  

  p < p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; PHYT < (ng· h/mL/mg) 0.0001 Turmipure > NOV > STE PHYT > STE TEP < NOV > Turmipure[Log10] STE Turmipure Turmipure AUC0-8 h  

  p <  

   

  p < 0.0001; p < 0.0001; p < 0.0265; p < 0.0001; p < 0.0001; PHYT < (ng· h/mL) 0.0001 NOV > STE PHYT < STE TEP < NOV > Turmipure [Log10]Turmipure Turmipure DN of AUC0- p = p < p < 0.0001;  

  p < 0.0001; p = 0.0158; p < 0.0001;  

  p = 0.0333; PHYT < infinity 0.0033* 0.0001 Turmipure > NOV > STEPHYT > STE TEP < Turmipure (ng · h/mL/mg) STE Turmipure [Log10]AUC0-infinity p =  

   

   

   

   

   

   

   

  (ng · h/mL) 0.0033* [Log10] Normalized p = p < p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p = 0.0018; PHYT <Cmax 0.040 

 * 0.0001 Turmipure > NOV > STE PHYT > STE TEP < NOV > Turmipure(ng/mL/mg) STE Turmipure Turmipure [Log10] Cmax (ng/mL) p = p <  

   

  p < 0.0001;  

   

  p < 0.0001;  

  [Log10] 0.040 

 * 0.0001 NOV > STE NOV > Turmipure Rel. bio.  

  p <  

   

   

   

  p < 0.0001; p < 0.0001; p = 0.0001; between 0 and 0.0001 TEP < NOV >PHYT < 24 h [Log10] Turmipure Turmipure Turmipure Rel. bio. between  

  p <  

   

   

   

  p < 0.0001; p < 0.0001; p < 0.0001; PHYT < 0 and 8 h 0.0001 TEP <NOV > Turmipure [Log10] Turmipure Turmipure Rel. bio. between p = p =  

   

   

   

  p = 0.0190;  

   

  0 and infinity 0.00 

 * 0.0002 TEP < [Log10] Turmipure Half-life  

  p =  

   

   

   

   

   

  p = 0.0062; PHYT > (minutes) 0.0010 Turmipure [Log10] Terminal  

  p =  

   

   

   

   

   

  p = 0.0062; PHYT < elimination 0.0010 Turmipure rate constant [Log10]Tmax (minutes)  

  p <  

   

  p < 0.0001;  

   

  p < 0.0001; p = 0.041 

 ; [Log10] 0.0001 NOV < STE NOV < PHYT > Turmipure Turmipure

indicates data missing or illegible when filed

TABLE 32 Analysis of DMC glucuronide (ng/mL) between products in the ITTpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP NOV PHYTTurmipure Turmipure Turmipure Endpoint effect effect vs STE vs STE vsSTE vs STE GOLD ™ GOLD ™ GOLD ™ DN of AUC0-24 h  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001;  

  (ng · h/mL/mg) Turmipure > NOV > PHYT > TEP < NOV > [Log10] STE STESTE Turmipure Turmipure AUC0-24 h  

  p < 0.0001  

   

  p = 0.0010;  

   

  p < 0.0001;  

  (ng · h/mL) NOV > NOV > [Log10] STE Turmipure DN of AUC0-8 h  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p = 0.0131; (ng ·h/mL/mg) Turmipure > NOV > PHYT > TEP < NOV > PHYT < [Log10] STE STE STETurmipure Turmipure Turmipure AUC0-8 h  

  p < 0.0001  

   

  p < 0.0001;  

   

  p < 0.0001;  

  (ng · h/mL) NOV > NOV > [Log10] STE Turmipure DN of AUC0-infinity  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p = 0.0135; p < 0.0001; p = 0.0187;  

  (ng · h/mL/mg) Turmipure > NOV > PHYT > TEP < NOV > [Log10] STE STESTE Turmipure Turmipure AUC0-infinity  

   

   

   

   

   

   

   

   

  (ng · h/mL) [Log10] Normalized Cmax  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p = 0.0066; p < 0.0001; p < 0.0001; p = 0.0 

 ; (ng/mL/mg) [Log10] Turmipure > NOV > PHYT > TEP < NOV > PHYT < STESTE STE Turmipure Turmipure Turmipure Cmax (ng/mL)  

  p < 0.0001  

   

  p < 0.0001;  

   

  p < 0.0001;  

  [Log10] NOV > NOV > STE Turmipure Rel. bio.  

  p < 0.0001  

   

   

   

  p < 0.0001; p < 0.0001;  

  between TEP < NOV > 0 and 24 h Turmipure Turmipure [Log10] Rel. bio.  

  p < 0.0001  

   

   

   

  p < 0.0001; p < 0.0001; p = 0.0207; between TEP < NOV > PHYT < 0 and 8h Turmipure Turmipure Turmipure [Log10] Rel. bio. between 0  

  p < 0.0001  

   

   

   

  p < 0.0001;  

   

  and infinity [Log10] TEP < Turmipure Half-life (minutes)  

  p = 0.0035  

   

   

   

   

   

   

  [Log10] Terminal elimination  

  p = 0.0002  

   

  p = 0.0008;  

   

  p = 0.02 

 2;  

  rate constant NOV > NOV > [Log10] STE Turmipure Tmax (minutes)  

  p = 0.0108  

   

   

   

   

   

   

  [Log10]

indicates data missing or illegible when filed

TABLE 33 Analysis of DMC sulfate (ng/mL) between products in the ITTpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT Visit Product GOLD ™ TEP NOV PHYT TurmipureTurmipure vs Turmipure Endpoint effect effect vs STE vs STE vs STE vsSTE GOLD ™ GOLD ™ GOLD ™ DN of AUC0-24 h  

  p < p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001;  

  p = 0.0003; (ng · h/mL/mg) 0.0001 Turmipure > NOV > PHYT > TEP < PHYT< [Log10] STE STE STE Turmipure Turmipure AUC0-24 h  

  p =  

   

  p = 0.00 

   

   

   

   

  (ng · h/mL) 0.0051 NOV < [Log10] STE DN of AUC0-8 h  

  p < p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001;  

  p < 0.0001; (ng · h/mL/mg) 0.0001 Turmipure > NOV > PHYT > TEP < PHYT< [Log10] STE STE STE Turmipure Turmipure AUC0-8 h  

   

   

   

   

   

   

   

   

  (ng · h/mL) [Log10] DN of  

  p < p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001;  

  p = 0.0101; AUC0-infinity 0.0001 Turmipure > NOV > PHYT > TEP < PHYT <(ng · h/mL/mg) STE STE STE Turmipure Turmipure [Log10] AUC0-infinity  

  p =  

   

  p = 0.0019;  

   

   

   

  (ng · h/mL) 0.0016 NOV < [Log10] STE Normalized  

  p < p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p = 0.0106; p < 0.0001; Cmax(ng/mL/ 0.0001 Turmipure > NOV > PHYT > TEP < NOV > PHYT < mg) [Log10]STE STE STE Turmipure Turmipure Turmipure Cmax (ng/mL)  

   

   

   

   

   

   

   

  [Log10] Rel. bio. between  

  p <  

   

   

   

  p < 0.0001;  

  p = 0.0007; 0 and 24 h 0.0001 TEP < PHYT < [Log10] Turmipure TurmipureRel. bio. between  

  p <  

   

   

   

  p < 0.0001;  

  p < 0.0001; 0 and 8 h 0.0001 TEP < PHYT < [Log10] Turmipure TurmipureRel. bio. between  

  p <  

   

   

   

  p < 0.0001;  

   

  0 and infinity 0.0001 TEP < [Log10] Turmipure Half-life (minutes)  

   

   

   

   

   

   

   

   

  [Log10] Terminal  

   

   

   

   

   

   

   

   

  elimination rate constant [Log10] Tmax (minutes)  

  p <  

   

  p < 0.0001;  

   

  p = 0.0022;  

  [Log10] 0.0001 NOV < NOV < STE Turmipure

indicates data missing or illegible when filed

TABLE 34 Analysis of DMC and its relative sulfate and glucuronidemetabolites (ng/mL) between products in the ITT population.Between-group analysis-Statistical significance of comparisons betweenproducts (adjusted p-value, Tukey adjustment) Turmipure TEP vs NOV vsPHYT vs Visit Product GOLD ™ TEP NOV PHYT Turmipure Turmipure TurmipureEndpoint effect effect vs STE vs STE vs STE vs STE GOLD ™ GOLD ™ GOLD ™DN of AUC0-24 h  

  p < p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p = 0.0293; p = 0.0005; (ng ·h/mL/mg) 0.0001 Turmipure > NOV > PHYT > TEP < NOV > PHYT < [Log10] STESTE STE Turmipure Turmipure Turmipure AUC0-24 h  

   

   

   

   

   

   

   

   

  (ng · h/mL) [Log10] DN of AUC0-8 h  

  p < p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; (ng ·h/mL/mg) 0.0001 Turmipure > NOV > PHYT > TEP < NOV > PHYT < [Log10] STESTE STE Turmipure Turmipure Turmipure AUC0-8 h  

  p =  

   

  p = 0.0112;  

   

  p = 0.0075;  

  (ng · h/mL) 0.00 

  NOV > NOV > [Log10] STE Turmipure DN of  

  p < p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001;  

  p < 0.0001; AUC0-infinity 0.0001 Turmipure > NOV > PHYT > TEP < PHYT <(ng · h/mL/mg) STE STE STE Turmipure Turmipure [Log10] AUC0-infinity  

  p =  

   

   

   

   

   

   

  (ng · h/mL) 0.0150 [Log10] Normalized  

  p < p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p = 0.00 

 ; Cmax (ng/mL/ 0.0001 Turmipure > NOV > PHYT > TEP < NOV > PHYT < mg)[Log10] STE STE STE Turmipure Turmipure Turmipure Cmax (ng/mL)  

  p <  

   

  p < 0.0001;  

   

  p < 0.0001;  

  [Log10] 0.0001 NOV > NOV > STE Turmipure Rel. bio.  

  p <  

   

   

   

  p < 0.0001;  

  p =  

 .0052; between 0.0001 TEP < PHYT < 0 and 24 h Turmipure Turmipure[Log10] Rel. bio.  

  p <  

   

   

   

  p < 0.0001; p = 0.0004; p < 0.0001; between 0 0.0001 TEP < NOV > PHYT< and 8 h Turmipure Turmipure Turmipure [Log10] Rel. bio.  

  p <  

   

   

   

  p < 0.0001;  

  p = 0.0006; between 0 and 0.0001 TEP < PHYT < infinity [Log10]Turmipure Turmipure Half-life  

  p =  

   

  p = 0.0019;  

   

  p = 0.0018;  

  (minutes) 0.0004 NOV < NOV < [Log10] STE Turmipure Terminal  

  p =  

   

  p = 0.0019;  

   

  p = 0.0018;  

  elimination 0.0004 NOV > NOV > rate constant STE Turmipure [Log10]Tmax (minutes)  

  p <  

   

  p  

 0001; p = 0.0117;  

  p = 0.0060; p = 0.0003; [Log10] 0.0001 NOV < PHYT > NOV < PHYT > STESTE Turmipure Turmipure

indicates data missing or illegible when filed

TABLE 35 Analysis of BDMC glucuronide (ng/mL) between products in theITT population. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP NOV PHYTTurmipure Turmipure Turmipure Endpoint effect effect vs STE vs STE vsSTE vs STE GOLD ™ GOLD ™ GOLD ™ DN of AUC0-24 h  

  p <  

   

  p < 0.0001;  

   

  p = 0.0001;  

  (ng · h/mL/mg) 0.0001 NOV > NOV > [Log10] STE Turmipure AUC0-24 h  

  p = p = 0.0003;  

   

   

   

  p = 0.0040;  

  (ng · h/mL) 0.0003 Turmipure < NOV > [Log10] STE Turmipure DN ofAUC0-8 h  

  p <  

   

  p < 0.0001;  

   

  p < 0.0001;  

  (ng · h/mL/mg) 0.0001 NOV > NOV > [Log10] STE Turmipure AUC0-8 h  

  p < p < 0.0003; p = 0.0290;  

  p = 0.000 

 ; p < 0.0153; p < 0.0001;  

  (ng · h/mL) 0.0001 Turmipure < TEP < PHYT < TEP > NOV > [Log10] STESTE STE Turmipure Turmipure DN of AUC0-infinity  

  p <  

   

  p = 0.000 

 ;  

   

  p = 0.0010;  

  (ng · h/mL/mg) 0.0001 NOV > NOV > [Log10] STE Turmipure AUC0-infinity 

  p = p = 0.0060;  

   

  p = 0.0263; p = 0.02 

 2; p = 0.0439;  

  (ng · h/mL) 0.0009 Turmipure < PHYT < TEP > NOV > [Log10] STE STETurmipure Turmipure Normalized Cmax  

  p <  

   

  p < 0.0001;  

  p = 0.0007; p < 0.0001;  

  (ng/mL/mg) [Log10] 0.0001 NOV > TEP < NOV > STE Turmipure TurmipureCmax (ng/mL)  

  p < p < 0.000 

 ; p = 0.00 

 ;  

  p < 0.0001;  

  p < 0.0001;  

  [Log10] 0.0001 Turmipure < TEP < PHYT < NOV > STE STE STE TurmipureRel. bio.  

  p <  

   

   

   

  p = 0.0291; p = 0.0005;  

  between 0 and 24 h 0.0001 TEP < NOV > [Log10] Turmipure Turmipure Rel.bio.  

  p <  

   

   

   

   

  p < 0.0001;  

  between 0 and 8 h 0.0001 NOV > [Log10] Turmipure Rel. bio. between 0  

  p =  

   

   

   

   

   

   

  and infinity [Log10] 0.0275 Half-life (minutes)  

  p < p = 0.0020;  

   

  p = 0.004 

 ; p = 0.0116; p = 0.0075;  

  [Log10] 0.0001 Turmipure < PHYT < TEP > NOV > STE STE TurmipureTurmipure Terminal elimination  

  p < p = 0.006 

 ; p = 0.0252;  

  p = 0.0015;  

  p < 0.0001;  

  rate constant 0.0001 Turmipure < TEP < PHYT < NOV > [Log10] STE STESTE Turmipure Tmax (minutes)  

  p =  

   

   

   

   

  p = 0.01 

 ;  

  [Log10] 0.0275 NOV > Turmipure

indicates data missing or illegible when filed

TABLE 36 Analysis of BDMC sulfate (ng/mL) between products in the ITTpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP NOV PHYTTurmipure Turmipure Turmipure Endpoint effect effect vs STE vs STE vsSTE vs STE GOLD ™ GOLD ™ GOLD ™ DN of AUC0-24 h  

  p = 0.0055  

   

   

   

  p = 0.023 

 ;  

   

  (ng · h/mL/mg) TEP < [Log10] Turmipure AUC0-24 h  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0008; p < 0.0001;  

  p = 0.0280; (ng · h/mL) Turmipure < NOV < PHYT < TEP > PHYT > [Log10]STE STE STE Turmipure Turmipure DN of AUC0-8 h  

  p < 0.0001  

   

  p = 0.0101;  

  p < 0.0001;  

   

  (ng · h/mL/mg) NOV > TEP < [Log10] STE Turmipure AUC0-8 h  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001;  

   

  (ng · h/mL) Turmipure < NOV < PHYT < TEP > [Log10] STE STE STETurmipure DN of AUC0-infinity  

   

   

   

   

   

   

   

   

  (ng · h/mL/mg) [Log10] AUC0-infinity  

  p < 0.0001 p < 0.0001;  

  p = 0.0002; p = 0.0059; p < 0.0001;  

   

  (ng · h/mL) Turmipure < NOV < PHYT < TEP > [Log10] STE STE STETurmipure Normalized Cmax p = 0.0424* p = 0.0248  

   

   

   

   

   

   

  (ng/mL/mg) [Log10] Cmax (ng/mL) p = 0.0300* p = 0.0029 p = 0.0109;  

  p = 0.0 

 2; p = 0.0109;  

   

   

  [Log10] Turmipure < NOV < PHYT < STE STE STE Rel. bio. between  

  p = 0.0320  

   

   

   

   

   

   

  0 and 24 h [Log10] Rel. bio. between  

  p = 0.0002  

   

   

   

  p = 0.0024;  

   

  0 and 8 h TEP < [Log10] Turmipure Rel. bio. between 0  

   

   

   

   

   

   

   

   

  and infinity [Log10] Half-life (minutes)  

  p < 0.0001 p < 0.0001;  

   

  p = 0.04 

 6; p < 0.00 

 1;  

   

  [Log10] Turmipure < PHYT < TEP > STE STE Turmipure Terminalelimination  

  p = 0.0012  

   

  p = 0.0021;  

   

   

   

  rate constant NOV > [Log10] STE Tmax (minutes)  

  p = 0.0219  

   

   

   

   

   

  p = 0.0367; [Log10] PHYT > Turmipure

indicates data missing or illegible when filed

TABLE 37 Analysis of BDMC and its relative sulfate and glucuronidemetabolites (ng/mL) between products in the ITT population.Between-group analysis-Statistical significance of comparisons betweenproducts (adjusted p-value, Tukey adjustment) Turmipure TEP vs NOV vsPHYT vs Visit Product GOLD ™ TEP NOV PHYT Turmipure Turmipure TurmipureEndpoint effect effect vs STE vs STE vs STE vs STE GOLD ™ GOLD ™ GOLD ™DN of AUC0-24 h  

  p < 0.0001  

   

  p = 0.00 

 0;  

  p = 0.0015;  

   

  (ng · h/mL/mg) NOV > TEP < [Log10] STE Turmipure AUC0-24 h  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p = 0.0004; p < 0.0001;  

  p = 0.0111; (ng · h/mL) Turmipure < NOV < PHYT < TEP > PHYT > [Log10]STE STE STE Turmipure Turmipure DN of AUC0-8 h  

  p < 0.0001 p < 0.0 

 01;  

  p < 0.0001;  

  p < 0.0001; p = 0.0452;  

  (ng · h/mL/mg) Turmipure > NOV > TEP < NOV > [Log10] STE STE TurmipureTurmipure AUC0-8 h  

  p < p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p = 0.0064;  

  (ng · h/mL) 0.000 

  Turmipure < NOV < PHYT < TEP > NOV > [Log10] STE STE STE TurmipureTurmipure DN of AUC0-infinity  

  p = 0.0033  

   

   

  p = 0.0350;  

   

   

  (ng · h/mL/mg) PHYT > [Log10] STE AUC0-infinity  

  p < 0.0001 p < 0.0001;  

  p = 0.0003;  

  p < 0.0001;  

  p = 0.01 

 8; (ng · h/mL) Turmipure < NOV < TEP > PHYT > [Log10] STE STE TurmipureTurmipure Normalized Cmax  

  p < 0.0001 p = 0.001 

 ;  

  p < 0.0001;  

  p < 0.0001; p < 0.0001; p = 0.0054; (ng/mL/mg) [Log10] Turmipure >NOV > TEP < NOV > PHYT < STE STE Turmipure Turmipure Turmipure Cmax(ng/mL)  

  p < 0.0001 p < 0.0001; p = 0.0010; p = 0.0086; p < 0.0001; p < 0.0001;p < 0.0001;  

  [Log10] Turmipure < TEP < NOV < PHYT < TEP > NOV > STE STE STE STETurmipure Turmipure Rel. bio. between  

  p = 0.0004  

   

   

   

  p = 0.0303;  

   

  0 and 24 h TEP < [Log10] Turmipure Rel. bio. between  

  p < 0.0001  

   

   

   

  p < 0.0001;  

   

  0 and 8 h TEP < [Log10] Turmipure Rel. bio. between 0  

  p =  

   

   

   

   

   

   

  and infinity [Log10] 0.04 

 3 Half-life (minutes)  

  p < 0.0001 p = 0.0025;  

  p = 0.0201;  

  p < 0.0001;  

  p = 0.0310; [Log10] Turmipure < NOV < TEP > PHYT > STE STE TurmipureTurmipure Terminal elimination  

  p < 0.0001  

   

  p < 0.0001;  

   

  p = 0.0003;  

  rate constant NOV > NOV > [Log10] STE Turmipure Tmax (minutes)  

  p =  

   

   

   

   

   

  p = 0.0 

 07; [Log10] 0 

 0133 PHYT > Turmipure

indicates data missing or illegible when filed

TABLE 38 Analysis of THC glucuronide (ng/mL) between products in the ITTpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP NOV PHYTTurmipure Turmipure Turmipure Endpoint effect effect vs STE vs STE vsSTE vs STE GOLD ™ GOLD ™ GOLD ™ DN of AUC0-24 h  

  p < p < 0.0001;  

  p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; (ng · h/mL/mg) 0.0001 Turmipure >NOV > TEP < NOV > PHYT < [Log10] STE STE Turmipure Turmipure TurmipureAUC0-24 h  

  p <  

   

  p = 0.0212; p < 0.0001; p = 0.028 

 ;  

  p < 0.0001; (ng · h/mL) 0.0001 NOV > PHYT < TEP < PHYT < [Log10] STESTE Turmipure Turmipure DN of AUC0-8 h  

  p < p < 0.0001;  

  p < 0.0001;  

  p  

  0.0001; p < 0.0001; p < 0.0001; (ng · h/mL/mg) 0.0001 Turmipure >NOV > TEP < NOV > PHYT < [Log10] STE STE Turmipure Turmipure TurmipureAUC0-8 h  

  p <  

   

  p = 0.000 

 ; p < 0.0001; p = 0.0020;  

  p < 0.0001; (ng · h/mL) 0.0001 NOV > STE PHYT < TEP < PHYT < [Log10]STE Turmipure Turmipure DN of AUC0-infinity  

  p < p < 0.0001;  

  p < 0.0001; p = 0.0387; p < 0.0001;  

  p < 0.0001; (ng · h/mL/mg) 0.0001 Turmipure > NOV > PHYT < TEP < PHYT< [Log10] STE STE STE Turmipure Turmipure AUC0-infinity  

  p <  

   

   

  p < 0.0001; p = 0.0171;  

  p < 0.0001; (ng · h/mL) 0.0001 PHYT < TEP < PHYT < [Log10] STETurmipure Turmipure Normalized Cmax  

  p < p < 0.0001;  

  p < 0.0001; p = 0.0173; p < 0.0001; p < 0.0001; p < 0.0001; (ng/mL/0.0001 Turmipure > NOV > PHYT > TEP < NOV > PHYT < mg) [Log10] STE STESTE Turmipure Turmipure Turmipure Cmax (ng/mL)  

  p <  

   

  p < 0.0001; p < 0.0001; p = 0.0359;  

  p < 0.0001; [Log10] 0.0001 NOV > PHYT < TEP < PHYT < STE STE TurmipureTurmipure Rel. bio.  

  p <  

   

   

   

  p < 0.0001; p = 0.0030; p < 0.0001; between 0 0.0001 TEP < NOV > PHYT< and 24 h Turmipure Turmipure Turmipure [Log10] Rel. bio.  

  p <  

   

   

   

  p < 0.0001; p < 0.0001; p < 0.0001; between 0 0.0001 TEP < NOV > PHYT< and 8 h Turmipure Turmipure Turmipure [Log10] Rel. bio.  

  p <  

   

   

   

  p < 0.0001;  

  p < 0.0001; between 0 and 0.0001 TEP < PHYT < infinity [Log10]Turmipure Turmipure Half-life (minutes)  

  p <  

   

   

  p < 0 

 0001;  

   

  p < 0.0001; [Log10] 0.0001 PHYT < STE PHYT < Turmipure Terminalelimination  

  p <  

   

   

   

   

   

   

  rate constant 0.0001 [Log10] Tmax (minutes)  

  p <  

   

   

  p = 0.0004;  

   

  p = 0.0003; [Log10] 0.0001 PHYT < STE PHYT < Turmipure

indicates data missing or illegible when filed

TABLE 39 Analysis of THC sulfate (ng/mL) between products in the ITTpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP NOV PHYTTurmipure Turmipure Turmipure Endpoint effect effect vs STE vs STE vsSTE vs STE GOLD ™ GOLD ™ GOLD ™ DN of AUC0-24 h p =  

   

   

   

   

   

   

   

  (ng · h/mL/mg) 0.0057* [Log10] AUC0-24 h p =  

   

   

   

   

   

   

   

  (ng · h/mL) 0.0328* [Log10] DN of AUC0-8 h p =  

   

   

   

   

   

   

   

  (ng · h/mL/mg) 0.0109* [Log10] AUC0-8 h  

  p < 0.0001  

   

   

  p = 0.0067;  

   

  p = 0.0003; (ng · h/mL) PHYT < PHYT < [Log10] STE Turmipure DN ofAUC0-infinity  

  p = 0.0013  

   

  p = 0.0327;  

   

   

   

  (ng · h/mL/mg) NOV > [Log10] STE AUC0-infinity  

  p = 0.0134  

   

   

   

   

   

   

  (ng · h/mL) [Log10] Normalized Cmax p = p = 0.0438  

   

   

   

   

   

   

  (ng/mL/mg) [Log10] 0.0007* Cmax (ng/mL)  

  p = 0.0006  

   

   

  p = 0.0315;  

   

  p = 0.0005; [Log10] PHYT < PHYT < STE Turmipure Rel. bio.  

  p = 0.0022  

   

   

   

   

   

   

  between 0 and 24 h [Log10] Rel. bio.  

  p < 0.0001  

   

   

   

  p = 0 

 0038;  

  p = 0.01 

 8; between 0 and 8 h TEP < PHYT < [Log10] Turmipure Turmipure Rel. bio.between 0  

   

   

   

   

   

   

   

   

  and infinity [Log10] Half-life (minutes)  

  p = 0.0134  

   

   

   

   

   

   

  [Log10] Terminal elimination  

  p = 0.0412  

   

   

   

   

   

  p = 0.0184; rate constant PHYT < [Log10] Turmipure Tmax (minutes) p = 

   

   

   

   

   

   

   

  [Log10] 0.0309*

indicates data missing or illegible when filed

TABLE 40 Analysis of HHC glucuronide (ng/mL) between products in the ITTpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP NOV PHYTTurmipure Turmipure Turmipure Endpoint effect effect vs STE vs STE vsSTE vs STE GOLD ™ GOLD ™ GOLD ™ DN of AUC0-24 h  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p = 0.0013; p < 0.0001; (ng ·h/mL/mg) Turmipure > NOV > PHYT > TEP < NOV > PHYT < [Log10] STE STE STETurmipure Turmipure Turmipure AUC0-24 h  

  p < 0.0001 p = 0.0002;  

  p < 0.0001; p < 0.0001; p < 0.0001;  

  p < 0.0001; (ng · h/mL) Turmipure > NOV > PHYT < TEP < PHYT < [Log10]STE STE STE Turmipure Turmipure DN of AUC0-8 h  

  p < 0.0001 p < 0.0001;  

  p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; (ng · h/mL/mg) Turmipure > NOV >TEP < NOV > PHYT < [Log10] STE STE Turmipure Turmipure Turmipure AUC0-8h  

  p < 0.0001 p = 0.0015;  

  p < 0.0001; p < 0.0001; p < 0.0001;  

  p < 0.0001; (ng · h/mL) Turmipure > NOV > PHYT < TEP < PHYT < [Log10]STE STE STE Turmipure Turmipure DN of AUC0-infinity  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p = 0.0352; p < 0.0001; p = 0.023 

 ; p < 0.0001; (ng · h/mL/mg) Turmipure > NOV > PHYT > TEP < NOV > PHYT< [Log10] STE STE STE Turmipure Turmipure Turmipure AUC0-infinity  

  p < 0.0001  

   

  p = 0.0133; p < 0.0001; p = 0.0192;  

  p < 0.0001; (ng · h/mL) NOV > PHYT < TEP < PHYT < [Log10] STE STETurmipure Turmipure Normalized Cmax  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; (ng/mL/mg)[Log10] Turmipure > NOV > PHYT > TEP < NOV > PHYT < STE STE STETurmipure Turmipure Turmipure Cmax (ng/mL)  

  p < 0.0001 p = 0.0002;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; [Log10]Turmipure > NOV > PHYT < TEP < NOV > PHYT < STE STE STE TurmipureTurmipure Turmipure Rel. bio.  

  p < 0.0001  

   

   

   

  p < 0.0001; p = 0.0 

 02; p < 0.0001; between 0 and 24 h TEP < NOV > PHYT < [Log10] TurmipureTurmipure Turmipure Rel. bio.  

  p < 0.0001  

   

   

   

  p < 0.0001; p < 0.0001; p < 0.0001; between 0 and 8 h TEP < NOV > PHYT< [Log10] Turmipure Turmipure Turmipure Rel. bio. between 0  

  p < 0.0001  

   

   

   

  p < 0.0001;  

  p < 0.0001; and infinity [Log10] TEP < PHYT < Turmipure TurmipureHalf-life (minutes)  

   

   

   

   

   

   

   

   

  [Log10] Terminal elimination  

   

   

   

   

   

   

   

   

  rate constant [Log10] Tmax (minutes)  

  p < 0.0001  

   

  p < 0.0001; p = 0.03 

 ;  

  p < 0.0001; p < 0.0001; [Log10] NOV < PHYT > NOV < PHYT > STE STETurmipure Turmipure

indicates data missing or illegible when filed

TABLE 41 Analysis of HHC sulfate (ng/mL) between products in the ITTpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP NOV PHYTTurmipure Turmipure Turmipure Endpoint effect effect vs STE vs STE vsSTE vs STE GOLD ™ GOLD ™ GOLD ™ DN of AUC0-24 h  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; (ng ·h/mL/mg) Turmipure > NOV > PHYT > TEP < NOV > PHYT < [Log10] STE STE STETurmipure Turmipure Turmipure AUC0-24 h  

  p < 0.0001 p = 0.0010;  

  p < 0.0001; p < 0.0001; p < 0.0001;  

  p < 0.0001; (ng · h/mL) Turmipure > NOV > PHYT < TEP < PHYT < [Log10]STE STE STE Turmipure Turmipure DN of AUC0-8 h  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p = 0.0 

 02; p < 0.0001; (ng · h/mL/mg) Turmipure > NOV > PHYT > TEP < NOV >PHYT < [Log10] STE STE STE Turmipure Turmipure Turmipure AUC0-8 h  

  p < 0.0001 p = 0.0002;  

  p < 0.0001; p < 0.0001; p < 0.0001;  

  p < 0.0001; (ng · h/mL) Turmipure > NOV > PHYT < TEP < PHYT < [Log10]STE STE STE Turmipure Turmipure DN of AUC0-infinity  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p = 0.000 

 ; p < 0.0001; (ng · h/mL/mg) Turmipure > NOV > PHYT > TEP < NOV > PHYT< [Log10] STE STE STE Turmipure Turmipure Turmipure AUC0-infinity  

  p < 0.0001  

   

  p = 0.0313; p < 0.0001; p = 0.0228;  

  p < 0.0001; (ng · h/mL) NOV > PHYT < TEP < PHYT < [Log10] STE STETurmipure Turmipure Normalized Cmax  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; (ng/mL/mg)[Log10] Turmipure > NOV > PHYT > TEP < NOV > PHYT < STE STE STETurmipure Turmipure Turmipure Cmax (ng/mL)  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; [Log10]Turmipure > NOV > PHYT < TEP < NOV > PHYT < STE STE STE TurmipureTurmipure Turmipure Rel. bio.  

  p < 0.0001  

   

   

   

  p < 0.0001; p < 0.0001; p < 0.0001; between 0 and 24 h TEP < NOV >PHYT < [Log10] Turmipure Turmipure Turmipure Rel. bio.  

  p < 0.0001  

   

   

   

  p < 0.0001; p = 0.0 

 08; p < 0.0001; between 0 and 8 h TEP < NOV > PHYT < [Log10] TurmipureTurmipure Turmipure Rel. bio. between 0 and  

  p < 0.0001  

   

   

   

  p < 0.0001; p = 0.0009; p < 0.0001; infinity [Log10] TEP < NOV > PHYT< Turmipure Turmipure Turmipure Half-life (minutes)  

  p < 0.0001 p = 0.0011;  

  p = 0.0011;  

  p = 0.0038;  

   

  [Log10] Turmipure < NOV < TEP > STE STE Turmipure Terminal elimination 

  p < 0.0001 p = 0.0011;  

  p = 0.0011;  

  p = 0.0038;  

   

  rate constant Turmipure > NOV > TEP < [Log10] STE STE Turmipure Tmax(minutes)  

  p < 0.0001  

   

  p < 0.0001; p < 0.0001;  

  p < 0.000 

 ; p < 0.0001; [Log10] NOV < PHYT > NOV < PHYT > STE STE TurmipureTurmipure

indicates data missing or illegible when filed

TABLE 42 Analysis of curcumin and all its relative metabolites (ng/mL)between products in the ITT population. Between-groupanalysis-Statistical significance of comparisons between products(adjusted p-value, Tukey adjustment) Turmipure TEP vs NOV vs PHYT vsVisit Product GOLD ™ TEP NOV PHYT Turmipure Turmipure Turmipure Endpointeffect effect vs STE vs STE vs STE vs STE GOLD ™ GOLD ™ GOLD ™ DN ofAUC0-24 h  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; (ng ·h/mL/mg) Turmipure > NOV > PHYT > TEP < NOV > PHYT < [Log10] STE STE STETurmipure Turmipure Turmipure AUC0-24 h  

  p < 0.0001 p = 0.0424;  

  p < 0.0001; p < 0.0001; p = 0.0005;  

  p < 0.0001; (ng · h/mL) Turmipure > NOV > PHYT < TEP < PHYT < [Log10]STE STE STE Turmipure Turmipure DN of AUC0-8 h  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; (ng ·h/mL/mg) Turmipure > NOV > PHYT > TEP < NOV > PHYT < [Log10] STE STE STETurmipure Turmipure Turmipure AUC0-8 h  

  p < 0.0001 p = 0.0002;  

  p < 0.0001; p < 0.0001; p < 0.0001; p = 0.0073; p < 0.0001; (ng ·h/mL) Turmipure > NOV > PHYT < TEP < NOV > PHYT < [Log10] STE STE STETurmipure Turmipure Turmipure DN of AUC0-infinity p = 0.0328* p < 0.0001p = 0.0003;  

  p < 0.0001;  

  p < 0.0001;  

  p = 0.0054; (ng · h/mL/mg) Turmipure > NOV > TEP < PHYT < [Log10] STESTE Turmipure Turmipure AUC0-infinity p = 0.0328* p = 0.0128  

   

   

  p = 0.047 

 ;  

   

   

  (ng · h/mL) PHYT < [Log10] STE Normalized Cmax  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; (ng/mL/mg)[Log10] Turmipure > NOV > PHYT > TEP < NOV > PHYT < STE STE STETurmipure Turmipure Turmipure Cmax (ng/mL)  

  p < 0.0001 p = 0.0009;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; [Log10]Turmipure > NOV > PHYT < TEP < NOV > PHYT < STE STE STE TurmipureTurmipure Turmipure Rel. bio. between  

  p < 0.0001  

   

   

   

  p < 0.0001; p < 0.0001; p < 0.0001; 0 and 24 h TEP < NOV > PHYT <[Log10] Turmipure Turmipure Turmipure Rel. bio. between  

  p < 0.0001  

   

   

   

  p < 0.0001; p < 0.0001; p < 0.0001; 0 and 8 h TEP < NOV > PHYT <[Log10] Turmipure Turmipure Turmipure Rel. bio. between p = 0 

 0102* p = 0.0002  

   

   

   

  p = 0.0007;  

  p = 0.0050; 0 and infinity TEP < PHYT < [Log10] Turmipure TurmipureHalf-life (minutes)  

  p < 0.0001 p = 0.0 

 36;  

  p = 0.0015;  

  p = 0.0111;  

  p = 0.0002; [Log10] Turmipure > NOV < TEP > PHYT > STE STE TurmipureTurmipure Terminal elimination  

  p < 0.0001 p = 0.0 

 36;  

  p = 0 

 ;  

  p = 0.0111;  

  p = 0.0002; rate constant Turmipure > NOV > TEP < PHYT < [Log10] STESTE Turmipure Turmipure Tmax (minutes)  

  p < 0.0001  

   

  p < 0.0001; p = 0.0297;  

  p < 0.0001; p = 0.0005; [Log10] NOV < PHYT > NOV < PHYT > STE STETurmipure Turmipure

indicates data missing or illegible when filed

TABLE 43 Analysis of total parent compounds and their relative sulfateand glucuronide metabolites (ng/mL) between products in the ITTpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP NOV PHYTTurmipure Turmipure Turmipure Endpoint effect effect vs STE vs STE vsSTE vs STE GOLD ™ GOLD ™ GOLD ™ DN of AUC0-24 h  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; (ng ·h/mL/mg) Turmipure > NOV > PHYT > TEP < NOV > PHYT < [Log10] STE STE STETurmipure Turmipure Turmipure AUC0-24 h  

  p < 0.0001  

   

   

  p < 0.0001;  

  p = 0.0057; p = 0.0005; (ng · h/mL) PHYT < NOV > PHYT < [Log10] STETurmipure Turmipure DN of AUC0-8 h  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; (ng ·h/mL/mg) Turmipure > NOV > PHYT > TEP < NOV > PHYT < [Log10] STE STE STETurmipure Turmipure Turmipure AUC0-8 h  

  p < 0.0001  

   

  p < 0.0001; p < 0.0001;  

  p < 0.0001; p < 0.0001; (ng · h/mL) NOV > PHYT < NOV > PHYT < [Log10]STE STE Turmipure Turmipure DN of AUC0-infinity  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p = 0.0142; p < 0.0001; (ng ·h/mL/mg) Turmipure > NOV > PHYT > TEP < NOV > PHYT < [Log10] STE STE STETurmipure Turmipure Turmipure AUC0-infinity  

  p = 0.00 

   

   

   

  p = 0.0047;  

   

   

  (ng · h/mL) PHYT < [Log10] STE Normalized Cmax  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; (ng/mL/mg)[Log10] Turmipure > NOV > PHYT > TEP < NOV > PHYT < STE STE STETurmipure Turmipure Turmipure Cmax (ng/mL)  

  p < 0.0001  

   

  p < 0.0001; p = 0.0022;  

  p < 0.0001; p = 0.0055; [Log10] NOV > PHYT < NOV > PHYT < STE STETurmipure Turmipure Rel. bio. between  

  p < 0.0001  

   

   

   

  p < 0.0001; p < 0.0001; p < 0.0001; 0 and 24 h TEP < NOV > PHYT <[Log10] Turmipure Turmipure Turmipure Rel. bio. between  

  p < 0.0001  

   

   

   

  p < 0.0001; p < 0.0001; p < 0.0001; 0 and 8 h TEP < NOV > PHYT <[Log10] Turmipure Turmipure Turmipure Rel. bio. p = 0.0397* p = 0.0151  

   

   

   

  p = 0.0447;  

   

  between 0 and TEP < infinity [Log10] Turmipure Half-life (minutes)  

  p = 0.0015 p = 0.0122;  

  p = 0.0032;  

   

   

   

  [Log10] Turmipure < NOV < STE STE Terminal elimination  

  p = 0.0015 p = 0.0122;  

  p = 0.0032;  

   

   

   

  rate constant Turmipure > NOV > [Log10] STE STE Tmax (minutes)  

  p < 0.0001  

   

  p < 0.0001; p = 0.0020;  

  p < 0.0001; p = 0.0099; [Log10] NOV < PHYT > NOV < PHYT > STE STETurmipure Turmipure

indicates data missing or illegible when filed

TABLE 44 Analysis of total curcunninoids (ng/mL) between products in thePP population. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP NOV PHYTTurmipure Turmipure Turmipure Endpoint effect effect vs STE vs STE vsSTE vs STE GOLD ™ GOLD ™ GOLD ™ DN of AUC0-24 h  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; (ng ·h/mL/mg) Turmipure > NOV > PHYT > TEP < NOV > PHYT < [Log10] STE STE STETurmipure Turmipure Turmipure AUC0-24 h  

  p < 0.0001  

   

  p < 0.0001; p < 0.0001; p = 0.0014;  

  p < 0.0001; (ng · h/mL) NOV > PHYT < TEP < PHYT < [Log10] STE STETurmipure Turmipure DN of AUC0-8 h  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; (ng ·h/mL/mg) Turmipure > NOV > PHYT > TEP < NOV > PHYT < [Log10] STE STE STETurmipure Turmipure Turmipure AUC0-8 h  

  p < 0.0001 p = 0.0012;  

  p < 0.0001; p < 0.0001; p < 0.0001; p = 0.0048; p < 0.0001; (ng ·h/mL) Turmipure > NOV > PHYT < TEP < NOV > PHYT < [Log10] STE STE STETurmipure Turmipure Turmipure DN of AUC0-infinity p = 0.0222* p < 0.0001p = 0.0003;  

  p < 0.0001;  

  p < 0.0001;  

  p = 0.00 

 ; (ng · h/mL/mg) Turmipure > NOV > TEP < PHYT < [Log10] STE STETurmipure Turmipure AUC0-infinity  

  p = 0.0007  

   

   

  p = 0.0032;  

   

  p = 0.0014; (ng · h/mL) PHYT < PHYT < [Log10] STE Turmipure NormalizedCmax  

  p < 0.0001 p < 0.0001;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; (ng/mL/mg)Turmipure > NOV > PHYT > TEP < NOV > PHYT < [Log10] STE STE STETurmipure Turmipure Turmipure Cmax (ng/mL)  

  p < 0.0001 p = 0.0009;  

  p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; [Log10]Turmipure > NOV > PHYT < TEP < NOV > PHYT < STE STE STE TurmipureTurmipure Turmipure Rel. bio. between  

  p < 0.0001  

   

   

   

  p < 0.0001; p < 0.0001; p < 0.0001; 0 and 24 h TEP < NOV > PHYT <[Log10] Turmipure Turmipure Turmipure Rel. bio. between  

  p < 0.0001  

   

   

   

  p < 0.0001; p < 0.0001; p < 0.0001; 0 and 8 h TEP < NOV > PHYT <[Log10] Turmipure Turmipure Turmipure Rel. bio.  

  p < 0.0001  

   

   

   

  p < 0.0001; p  

  0.0001; p < 0.0001; between 0 and TEP < NOV > PHYT < infinity [Log10]Turmipure Turmipure Turmipure Half-life (minutes)  

  p < 0.0001 p = 0.0062;  

  p = 0.002 

 ;  

  p = 0.0335;  

  p = 0.0010; [Log10] Turmipure < NOV < TEP > PHYT > STE STE TurmipureTurmipure Terminal elimination  

  p < 0.0001 p = 0.013 

 ;  

  p = 0.0034;  

  p = 0.0058;  

  p = 0.000 

 ; rate constant Turmipure > NOV > TEP < PHYT < [Log10] STE STETurmipure Turmipure Tmax (minutes)  

  p < 0.0001  

   

  p < 0.0001; p = 0.0282;  

  p < 0.0001; p = 0.0002; [Log10] NOV < PHYT > NOV < PHYT > STE STETurmipure Turmipure

indicates data missing or illegible when filed

TABLE 45 Analysis of curcumin (ng/mL) between products in the PPpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment) TEP vsNOV vs PHYT vs Visit Product Turmipure PHYT vs Turmipure TurmipureTurmipure Endpoint effect effect GOLD ™ vs STE TEP vs STE NOV vs STE STEGOLD ™ GOLD ™ GOLD ™ DN of AUC0-24 h

p = 0.0002 p = 0.0009;

p =  

 ;

p = 0.0010;

(ng · h/mL/mg) Turmipure  

  STE NOV  

  STE TEP  

  [Log10] Turmipure AUC0-24 h

(ng · h/mL/mg) [Log10] DN of AUC0-8 h p = 0.0107*

(ng · h/mL/mg) [Log10] AUC0-4 h

(ng · h/mL/mg) [Log10] DN of AUC0-infinity p = 0.0209*

(ng · h/mL/mg) [Log10] AUC0-infinity

(ng · h/mL/mg) [Log10] Normalized Cmax p = 0.0126*

(ng · h/mL/mg) [Log10] Cmax

(ng/mL) [Log10] Rel. bio. between

0 and 24 h [Log10] Rel. bio between

p = 0.0128

p =  

 ;

0 and 8 h TEP  

  [Log10] Turmipure Rel. bio. between

0 and infinity [Log10] Half-life (minutes)

[Log10] Terminal elimination

rate constant [Log10] Tmax (minutes)

[Log10]

indicates data missing or illegible when filed

TABLE 46 Analysis of curcumin glucuronide (ng/mL) between products inthe PP population. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP vs NOV vs PHYTvs Turmipure Turmipure Turmipure Endpoint effect effect vs STE STE STESTE GOLD ™ GOLD ™ GOLD ™ DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; AUC0-24 h Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-24 h

p

 0.0001

p

 0.0001; p

 0.0002;

p

 0.0001; p

 0.0002; (ng · h/mL) NOV > PHYT < NOV > PHYT < [Log10] STE STE TurmipureTurmipure DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0120; p

 0.0001; p

 0.0001; p

 0.0001; AUC0-8 h Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-8 h

p

 0.0001

p

 0.0001; p

 0.0001;

p

 0.0001; p

 0.0001; (ng · h/mL) NOV > PHYT > NOV > PHYT < [Log10] STE STE TurmipureTurmipure DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001;

AUC0-infinity Turmipure > NOV > PHYT > TEP < NOV > (ng · h/mL/mg) STESTE STE Turmipure Turmipure [Log10] AUC0-infinity

(ng · h/mL) [Log10] Normalized

p

 0.0001 p

 0.0001;

p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0042; Cmax Turmipure > NOV > TEP < NOV > PHYT < (ng/mL/mg) STE STETurmipure Turmipure Turmipure [Log10] Cmax

p

 0.0001

p

 0.0001; p

 0.0401;

p

 0.0001; p

 0.0004; (ng/mL) NOV > PHYT < NOV > PHYT < [Log10] STE STE TurmipureTurmipure Rel. bio.

p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0001; between TEP < NOV > PHYT < 0 and 24 h Turmipure TurmipureTurmipure [Log10] Rel. bio.

p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0001; between TEP < NOV > PHYT < 0 and 8 h Turmipure TurmipureTurmipure [Log10] Rel bio.

p

 0.0001

p

 0.0001; p

 0.0001;

between TEP < NOV > 0 and infinity Turmipure Turmipure [Log10] Half-life

p

 0.0001 p

 0.0157;

p

 0.0002;

p

 0.0132; (minutes) Turmipure < NOV < PHYT > [Log10] STE STE TurmipureTerminal

p

 0.0001 p

 0.0015;

p

 0.0001;

p

 0.0123; elimination Turmipure > NOV > PHYT < rate constant STE STETurmipure [Log10] Tmax

p

 0.0001

p

 0.0047;

p

;

(minutes) NOV < NOV < [Log10] STE Turmipure

indicates data missing or illegible when filed

TABLE 47 Analysis of curcumin sulfate (ng/mL) between products in the PPpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP vs NOV vs PHYTvs Turmipure Turmipure Turmipure Endpoint effect effect vs STE STE STESTE GOLD ™ GOLD ™ GOLD ™ DN of p = 0.027

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

; p

 0.0003; AUC0-24 h Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-24 h p =0.0024

(ng · h/mL) [Log10] DN of p = 0.028

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0; p

 0.0001; p

 0.001; p

 0.0001; AUC0-8 h Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-8 h p =0.0153

p

 0.0001

(ng · h/mL) [Log10] DN of p = 0.03

p

 0.0001 p

 0.0013;

p

 0.0001;

p

 0.0014;

AUC0-infinity Turmipure > NOV > TEP < (ng · h/mL/mg) STE STE Turmipure[Log10] AUC0-infinity

(ng · h/mL) [Log10] Normalized p = 0.02

p

 0.0001 p

 ;

p

 0.0001;

p

 0.0011; p

 0.0001; p

 0.0253; Cmax Turmipure > NOV > TEP < NOV > PHYT < (ng/mL/mg) STE STETurmipure Turmipure Turmipure [Log10] Cmax p = 0.0001

p

 0.0001

p

 0.0017;

p

 0.0022;

(ng/mL) NOV > NOV > [Log10] STE Turmipure Rel. bio.

p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0001; between TEP < NOV > PHYT < 0 and 24 h Turmipure TurmipureTurmipure [Log10] Rel. bio.

p

 0.0001

p

 0.0001; p

 0.0002; p

 0.0001; between TEP < NOV > PHYT < 0 and 8 h Turmipure TurmipureTurmipure [Log10] Rel bio. p = 0.0294

p

 0.0001

between 0 and infinity [Log10] Half-life

(minutes) [Log10] Terminal

p

 0.0122

elimination rate constant [Log10] Tmax

p

 0.0001

p

 0.0001;

p

 ; p

 0.0001; p

 0.0033; (minutes) NOV > TEP > NOV < PHYT > [Log10] STE TurmipureTurmipure Turmipure

indicates data missing or illegible when filed

TABLE 48 Analysis of curcumin and its relative sulfate and glucuronidematabolites (ng/mL) between products in the PP population. Between-groupanalysis-Statistical significance of comparisons between products(adjusted p-value, Tukey adjustment) Turmipure TEP vs NOV vs PHYT vsVisit Product GOLD ™ TEP vs NOV vs PHYT vs Turmipure Turmipure TurmipureEndpoint effect effect vs STE STE STE STE GOLD ™ GOLD ™ GOLD ™ DN of p =0.043

p

  p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 ; p

 0.0001; AUC0-24 h Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-24 h p =0.03

p

 0.0326

(ng · h/mL)

[Log10]

DN of p = 0.0294

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.026; p

 0.0001; p

 0.0001; p

 0.0001; AUC0-8 h Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-8 h

p

 0.0001

p

 0.0001; p

 0.0001;

p

 0.0001; p

 0.0001; (ng · h/mL) NOV > PHYT > NOV > PHYT < [Log10] STE STE TurmipureTurmipure DN of p = 0.0025

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0338; p

 0.0001; p

 0.0493; p

 0.0001; AUC0-infinity Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-infinityp = 0.001

(ng · h/mL) [Log10] Normalized p = 0.0164

p

 0.0001 p

 0.018;

p

 0.0001;

p

 0.0015; p

 0.0001;

Cmax Turmipure > NOV > TEP < NOV > (ng/mL/mg) STE STE TurmipureTurmipure [Log10]

Cmax p = 0.0

p

 0.0001

p

 0.0001;

p

 0.0001;

(ng/mL) NOV > NOV > [Log10] STE Turmipure Rel. bio.

p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0001; between TEP < NOV > PHYT < 0 and 24 h Turmipure TurmipureTurmipure [Log10] Rel. bio.

p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0001; between TEP < NOV > PHYT < 0 and 8 h Turmipure TurmipureTurmipure [Log10] Rel bio. p - 0.0047

p

 0.0001

p

 0.0001;

between TEP < 0 and infinity Turmipure [Log10] Half-life

p

 0.0001

p

 ; (minutes) PHYT < [Log10] Turmipure Terminal

p

 0.0001

p

 0.0202;

p

 0.0027; elimination NOV > PHYT < rate constant STE Turmipure [Log10]Tmax

p

 0.0001

p

 0.0001;

p

 0.0001;

(minutes) NOV < NOV < [Log10] STE Turmipure

indicates data missing or illegible when filed

TABLE 49 Analysis of DMC glucuronide (ng/mL) between products in the PPpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP vs NOV vs PHYTvs Turmipure Turmipure Turmipure Endpoint effect effect vs STE STE STESTE GOLD ™ GOLD ™ GOLD ™ DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001;

AUC0-24 h Turmipure > NOV > PHYT > TEP < NOV > (ng · h/mL/mg) STE STESTE Turmipure Turmipure [Log10] AUC0-24 h

p

 0.0001

p

 0.0001;

p

 0.0001;

(ng · h/mL) NOV > NOV > [Log10] STE Turmipure DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0138; AUC0-8 h Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-8 h

p

 0.0001

p

 0.0001;

p

 0.0001;

(ng · h/mL) NOV > NOV > [Log10] STE Turmipure DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0143; p

 0.0001; p

 0.0107;

AUC0-infinity Turmipure > NOV > PHYT > TEP < NOV > (ng · h/mL/mg) STESTE STE Turmipure Turmipure [Log10] AUC0-infinity

(ng · h/mL) [Log10] Normalized

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0068; p

 0.0001; p

 0.0001; p

 0.0312; Cmax Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng/mL/mg) STESTE STE Turmipure Turmipure Turmipure [Log10] Cmax

p

 0.0001

p

 0.0001;

p

 0.0001;

(ng/mL) NOV > NOV > [Log10] STE Turmipure Rel. bio.

p

 0.0001

p

 0.0001; p

 0.0001;

between TEP < NOV > 0 and 24 h Turmipure Turmipure [Log10] Rel. bio.

p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0216; between TEP < NOV > PHYT < 0 and 8 h Turmipure TurmipureTurmipure [Log10] Rel bio.

p

 0.0001

p

 0.0003;

between TEP < 0 and infinity Turmipure [Log10] Half-life

p

 0.0050

(minutes) [Log10] Terminal

p

 0.0002

p

 0.0006;

p

 0.0276;

elimination NOV > NOV > rate constant STE Turmipure [Log10] Tmax

p

 0.0086

(minutes) [Log10]

indicates data missing or illegible when filed

TABLE 50 Analysis of DMC sulfate (ng/mL) between products in the PPpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP vs NOV vs PHYTvs Turmipure Turmipure Turmipure Endpoint effect effect vs STE STE STESTE GOLD ™ GOLD ™ GOLD ™ DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001;

p

 0.001; AUC0-24 h Turmipure > NOV > PHYT > TEP < PHYT < (ng · h/mL/mg)STE STE STE Turmipure Turmipure [Log10] AUC0-24 h

p

 0.0001

p

 0.0068;

(ng · h/mL) NOV < [Log10] STE DN of p = 0.0310

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0002; p

 0.0001;

p

 0.0231; AUC0-8 h Turmipure > NOV > PHYT > TEP < PHYT < (ng · h/mL/mg)STE STE STE Turmipure Turmipure [Log10] AUC0-8 h

(ng · h/mL) [Log10] DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001;

p

 0.0021; AUC0-infinity Turmipure > NOV > PHYT > TEP < PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure [Log10] AUC0-infinity p

 0.0016

p

 0.0021;

(ng · h/mL) NOV < [Log10] STE Normalized

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0016; p

 0.082; Cmax Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng/mL/mg) STESTE STE Turmipure Turmipure Turmipure [Log10] Cmax

(ng/mL) [Log10] Rel. bio.

p

 0.0001

p

 0.0001;

p

 0.0015; between TEP < PHYT < 0 and 24 h Turmipure Turmipure [Log10]Rel. bio.

p

 0.0001

p

 0.0001;

p

 0.0001; between TEP < PHYT < 0 and 8 h Turmipure Turmipure [Log10] Relbio.

p

 0.0001

p

 0.0001;

between TEP < 0 and infinity Turmipure [Log10] Half-life

(minutes) [Log10] Terminal

elimination rate constant [Log10] Tmax

p

 0.0001

p

 0.0001;

p

 0.0023;

(minutes) NOV < NOV < [Log10] STE Turmipure

indicates data missing or illegible when filed

TABLE 51 Analysis of DMC and its relative sulfate and glucuronidemetabolites (ng/mL) between products in the PP population. Between-groupanalysis-Statistical significance of comparisons between products(adjusted p-value, Tukey adjustment) Turmipure TEP vs NOV vs PHYT vsVisit Product GOLD ™ TEP vs NOV vs PHYT vs Turmipure Turmipure TurmipureEndpoint effect effect vs STE STE STE STE GOLD ™ GOLD ™ GOLD ™ DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0035; p

 0.0001; AUC0-24 h Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-24 h

(ng · h/mL) [Log10] DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; AUC0-8 h Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-8 h

p

 0.0001

p

 0.0078;

p

 0.0057;

(ng · h/mL) NOV > NOV > [Log10] STE Turmipure DN of

p

 0.0001 p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0001;

p

 0.0001; AUC0-infinity Turmipure > NOV > PHYT > TEP < PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure [Log10] AUC0-infinity

p

 0.0138

(ng · h/mL) [Log10] Normalized

p

 0.0001 p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0072; Cmax Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng/mL/mg) STESTE STE Turmipure Turmipure Turmipure [Log10] Cmax

p

 0.0001

p

 0.0001;

p

 0.0001;

(ng/mL) NOV > NOV > [Log10] STE Turmipure Rel. bio.

p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0191; between TEP < NOV > PHYT < 0 and 24 h Turmipure TurmipureTurmipure [Log10] Rel. bio.

p

 0.0001

p

 0.001; p

 0.0001; p

 0.0001; between TEP < NOV > PHYT < 0 and 8 h Turmipure TurmipureTurmipure [Log10] Rel bio.

p

 0.0001

p

 0.001;

p

 0.0047; between TEP < PHYT < 0 and infinity Turmipure Turmipure [Log10]Half-life

p

 0.0004

p

 0.0016;

p

 0.0018;

(minutes) NOV < NOV < [Log10] STE Turmipure Terminal

p

 0.0002

p

 0.0040;

p

 0.0002;

elimination NOV > NOV > rate constant STE Turmipure [Log10] Tmax

p

 0.0001

p

 0.0001; p

 0.0073; p

 0.0150; p

 0.0030; p

 0.0032; (minutes) NOV < PHYT > TEP > NOV < PHYT > [Log10] STE STETurmipure Turmipure Turmipure

indicates data missing or illegible when filed

TABLE 52 Analysis of BDMC glucuronide (ng/mL) between products in the PPpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP vs NOV vs PHYTvs Turmipure Turmipure Turmipure Endpoint effect effect vs STE STE STESTE GOLD ™ GOLD ™ GOLD ™ DN of

p

 0.0001

p

 0.0001;

p

 0.0261;

AUC0-24 h NOV > NOV > (ng · h/mL/mg) STE Turmipure [Log10] AUC0-24 h

p

 0.0003 p

 0.0003;

p

 0.0341;

(ng · h/mL) Turmipure < NOV > [Log10] STE Turmipure DN of

p

 0.0001

p

 0.0001;

p

 0.0201;

AUC0-8 h NOV > NOV > (ng · h/mL/mg) STE Turmipure [Log10] AUC0-8 h

p

 0.0001 p

 0.0001; p

 0.0367;

p

 0.0001; p

 0.0158; p

 0.0001;

(ng · h/mL) Turmipure < TEP < PHYT < TEP > NOV > [Log10] STE STE STETurmipure Turmipure DN of

p

 0.0001

p

 ;

p

 0.0009;

AUC0-infinity NOV > NOV > (ng · h/mL/mg) STE Turmipure [Log10]AUC0-infinity

p

 0.0003 p

 0.0089;

p

 0.0475; p

 0.0202; p

 0.0422;

(ng · h/mL) Turmipure < PHYT < TEP > NOV > [Log10] STE STE TurmipureTurmipure Normalized

p

 0.0001

p

 0.0001;

p

 0.0009; p

 0.0601;

Cmax NOV > TEP < NOV > (ng/mL/mg) STE Turmipure Turmipure [Log10] Cmax

p

 0.0001 p

 0.0001 p

 0.0035;

p

 0.0001;

p

 0.0001;

(ng/mL) Turmipure < TEP < PHYT < NOV > [Log10] STE STE STE TurmipureRel. bio.

p

 0.0001

p

 0.0337; p

 ;

between TEP < NOV > 0 and 24 h Turmipure Turmipure [Log10] Rel. bio.

p

 0.0001

p

 0.0001;

between NOV > 0 and 8 h Turmipure [Log10] Rel bio.

p

 0.0383

between 0 and infinity [Log10] Half-life

p

 0.0001 p

 0.0024;

p

 0.0003; p

 0.0137; p

 0.0272;

(minutes) Turmipure < PHYT < TEP > NOV > [Log10] STE STE TurmipureTurmipure Terminal

p

 0.0001 p

 0.0050; p

 0.0174;

p

 0.0003;

p

 0.0001; elimination Turmipure < TEP < PHYT < NOV >

rate constant STE STE STE Turmipure [Log10] Tmax

p

 0.0079

p

 1.0176;

(minutes) NOV > [Log10] Turmipure

indicates data missing or illegible when filed

TABLE 53 Analysis of BDMC sulfate (ng/mL) between products in the PPpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP vs NOV vs PHYTvs Turmipure Turmipure Turmipure Endpoint effect effect vs STE STE STESTE GOLD ™ GOLD ™ GOLD ™ DN of

p

 0.0012

p

 0.6931;

AUC0-24 h TEP < (ng · h/mL/mg) Turmipure [Log10] AUC0-24 h

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0081; p

 ;

p

 0.0057; (ng · h/mL) Turmipure < NOV < PHYT < TEP > PHYT > [Log10] STESTE STE Turmipure Turmipure DN of

p

 0.0001

p

 0.0151;

p

 ;

AUC0-8 h NOV > TEP < (ng · h/mL/mg) STE Turmipure [Log10] AUC0-8 h

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001;

(ng · h/mL) Turmipure < NOV < PHYT < TEP > [Log10] STE STE STE TurmipureDN of

AUC0-infinity (ng · h/mL/mg) [Log10] AUC0-infinity p = 0.0428

p

 0.0105 p

 0.0305;

(ng · h/mL) Turmipure < [Log10] STE Normalized p = 0.0213

p

 0.0248

Cmax (ng/mL/mg) [Log10] Cmax p = 0.01

p

 0.0029 p

 0.0109;

p

 0.00952; p

 0.0108;

(ng/mL) Turmipure < NOV < PHYT < [Log10] STE STE STE Rel. bio.

p

 0.0035

between 0 and 24 h [Log10] Rel. bio.

p

 0.0003

p

 0.033;

between TEP < 0 and 8 h Turmipure [Log10] Rel bio.

between 0 and infinity [Log10] Half-life

p

 0.0001 p

 0.0001;

p

 0.0382; p

 0.0001;

(minutes) Turmipure < PHYT < TEP > [Log10] STE STE Turmipure Terminal

p

 0.0013

p

 0.0024;

elimination NOV > rate constant STE [Log10] Tmax

p

 0.0182

p

 0.0474;

p

 0.0147; (minutes) TEP > PHYT > [Log10] Turmipure Turmipure

indicates data missing or illegible when filed

TABLE 54 Analysis of BDMC and its relative sulfate and glucuronidemetabolites (ng/mL) between products in the PP population. Between-groupanalysis-Statistical significance of comparisons between products(adjusted p-value, Tukey adjustment) Turmipure TEP vs NOV vs PHYT vsVisit Product GOLD ™ TEP vs NOV vs PHYT vs Turmipure Turmipure TurmipureEndpoint effect effect vs STE STE STE STE GOLD ™ GOLD ™ GOLD ™ DN of

p

 0.0001

p

 0.0053;

p

 0.0002;

AUC0-24 h NOV > TEP < (ng · h/mL/mg) STE Turmipure [Log10] AUC0-24 h

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0022; p

 0.0002;

p

 0.013; (ng · h/mL) Turmipure < NOV < PHYT < TEP > PHYT > [Log10] STESTE STE Turmipure Turmipure DN of

p

 0.0001 p

 0.0139;

p

 0.0001;

p

 0.0001; p

 0.0453;

AUC0-8 h Turmipure > NOV < TEP < NOV > (ng · h/mL/mg) STE STE TurmipureTurmipure [Log10] AUC0-8 h

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0065;

(ng · h/mL) Turmipure < NOV < PHYT < TEP < NOV > [Log10] STE STE STETurmipure Turmipure DN of

p

 0.0041

p

 0.0334;

AUC0-infinity PHYT > (ng · h/mL/mg) STE [Log10] AUC0-infinity

p

 0.0001

p

 ;

p

 0.0001;

p

 0.0157; (ng · h/mL) Turmipure < NOV < TEP > PHYT > [Log10] STE STETurmipure Turmipure Normalized

p

 0.0001 p

 0.0031 p

 0.0212; p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0005; Cmax Turmipure > TEP < NOV > TEP > NOV > PHYT < (ng/mL/mg) STESTE STE Turmipure Turmipure Turmipure [Log10] Cmax

p

 0.0001 p

 0.2081 p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001;

(ng/mL) Turmipure < TEP < NOV > PHYT < TEP > NOV > [Log10] STE STE STESTE Turmipure Turmipure Rel. bio.

p

 0.0001

p

 0.042;

between TEP < 0 and 24 h Turmipure [Log10] Rel. bio.

p

 0.0001

p

 0.0001;

between TEP < 0 and 8 h Turmipure [Log10] Rel bio.

between 0 and infinity [Log10] Half-life

p

 0.0001 p

 0.0157;

p

 0.0237;

p

 0.0001;

p

 0.0308; (minutes) Turmipure < NOV < TEP > PHYT > [Log10] STE STETurmipure Turmipure Terminal

p

 0.0001

p

 0.0001;

p

 0.0007;

elimination NOV > NOV > rate constant STE Turmipure [Log10] Tmax

p

 0.0001

p

 0.0299;

p

 0.0943; (minutes) PHYT > PHYT > [Log10] STE Turmipure

indicates data missing or illegible when filed

TABLE 55 Analysis of THC glucuronide (ng/mL) between products in the PPpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP vs NOV vs PHYTvs Turmipure Turmipure Turmipure Endpoint effect effect vs STE STE STESTE GOLD ™ GOLD ™ GOLD ™ DN of

p

 0.0001 p

 0.0001; p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; AUC0-24 h Turmipure > NOV > TEP < NOV > PHYT < (ng · h/mL/mg)STE STE Turmipure Turmipure Turmipure [Log10] AUC0-24 h

p

 0.0001

p

 0.0211; p

 0.0001; p

 0.0215;

p

 0.0001; (ng · h/mL) NOV > PHYT < TEP < PHYT < [Log10] STE STE TurmipureTurmipure DN of

p

 0.0001 p

 0.0001;

p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; AUC0-8 h Turmipure > NOV > TEP < NOV > PHYT < (ng · h/mL/mg)STE STE Turmipure Turmipure Turmipure [Log10] AUC0-8 h

p

 0.0001

p

 0.0009; p

 0.0001; p

 0.0016;

p

 0.0001; (ng · h/mL) NOV > PHYT < TEP < PHYT < [Log10] STE STE TurmipureTurmipure DN of

p

 0.0001 p

 0.0001

p

 0.0001; p

 0.0387; p

 0.0;

p

 0.0001; AUC0-infinity Turmipure > NOV > PHYT < TEP < PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure [Log10] AUC0-infinity

p

 0.0001; p

 0.0171;

p

 0.0001; (ng · h/mL) PHYT < TEP < PHYT < [Log10] STE Turmipure TurmipureNormalized

p

 0.0001 p

 0.0001

p

 0.0001; p

 0.0182; p

 0.0001; p

 0.0001; p

 0.0001; Cmax Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng/mL/mg) STESTE STE Turmipure Turmipure Turmipure [Log10] Cmax

p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0252;

p

 0.0001; (ng/mL) NOV > PHYT > TEP < PHYT < [Log10] STE STE TurmipureTurmipure Rel. bio.

p

 0.0001

p

 0.0001; p

 0.0029; p

 0.0001; between TEP < NOV > PHYT < 0 and 24 h Turmipure TurmipureTurmipure [Log10] Rel. bio.

p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0001; between TEP < NOV > PHYT < 0 and 8 h Turmipure TurmipureTurmipure [Log10] Rel bio.

p

 0.0001

p

 0.0001;

p

 0.0001; between TEP < PHYT < 0 and infinity Turmipure Turmipure [Log10]Half-life

p

 0.0001

p

 0.0001;

p

 0.0001; (minutes) PHYT < PHYT < [Log10] STE Turmipure Terminal

p

 0.0054

elimination rate constant [Log10] Tmax

p

 0.0001

p

 0.0003;

p

 0.0003; (minutes) PHYT < PHYT < [Log10] STE Turmipure

indicates data missing or illegible when filed

TABLE 56 Analysis of THC sulfate (ng/mL) between products in the PPpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP vs NOV vs PHYTvs Turmipure Turmipure Turmipure Endpoint effect effect vs STE STE STESTE GOLD ™ GOLD ™ GOLD ™ DN of p = 0.00

AUC0-24 h (ng · h/mL/mg) [Log10] AUC0-24 h p = 0.0306

(ng · h/mL) [Log10] DN of p = 0.0115

AUC0-8 h (ng · h/mL/mg) [Log10] AUC0-8 h

p

 0.0023

p

 ;

p

 0.0003; (ng · h/mL) PHYT < PHYT < [Log10] STE Turmipure DN of

p

 0.0029

p

 ;

AUC0-infinity NOV > (ng · h/mL/mg) STE [Log10] AUC0-infinity

p

 0.0125

(ng · h/mL) [Log10] Normalized p = 0.0004

p

 0.0438

Cmax (ng/mL/mg) [Log10] Cmax

p

 0.0005

p

 0.0204;

p

 0.005; (ng/mL) PHYT < PHYT < [Log10] STE Turmipure Rel. bio.

p

 0.0023

between 0 and 24 h [Log10] Rel. bio.

p

 0.0001

p

 0.0041;

p

 0.0121; between TEP < PHYT < 0 and 8 h Turmipure Turmipure [Log10] Relbio.

between 0 and infinity [Log10] Half-life

p

 0.0098

(minutes) [Log10] Terminal

p

 0.0349

p

 0.0151; elimination PHYT < rate constant Turmipure [Log10] Tmax p =0.0261

(minutes) [Log10]

indicates data missing or illegible when filed

TABLE 57 Analysis of HHC glucuronide (ng/mL) between products in the PPpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP vs NOV vs PHYTvs Turmipure Turmipure Turmipure Endpoint effect effect vs STE STE STESTE GOLD ™ GOLD ™ GOLD ™ DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; AUC0-24 h Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-24 h

p

 0.0001 p

 ;

p

 0.0001; p

 0.0001; p

 0.0001;

p

 0.0001; (ng · h/mL) Turmipure > NOV > PHYT < TEP < PHYT < [Log10] STESTE STE Turmipure Turmipure DN of

p

 0.0001 p

 0.0001;

p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; AUC0-8 h Turmipure > NOV > TEP < NOV > PHYT < (ng · h/mL/mg)STE STE Turmipure Turmipure Turmipure [Log10] AUC0-8 h

p

 0.0001 p

 0.0010;

p

 0.0001; p

 0.0001; p

 0.0001;

p

 0.0001; (ng · h/mL) Turmipure > NOV < PHYT < TEP < PHYT < [Log10] STESTE STE Turmipure Turmipure DN of

p

 0.0001 p

 0.0001;

p

 0.0001;

p

 0.0001; p

 0.0005; p

 0.0001; AUC0-infinity Turmipure > NOV > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE Turmipure Turmipure Turmipure [Log10] AUC0-infinity

p

 0.0001

p

 ; p

 0.0001; p

 0.0032;

p

 0.0001; (ng · h/mL) NOV > PHYT < TEP < PHYT < [Log10] STE STE TurmipureTurmipure Normalized

p

 0.0001 p

 0.0001;

p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; Cmax Turmipure > NOV > TEP < NOV > PHYT < (ng/mL/mg) STE STETurmipure Turmipure Turmipure [Log10] Cmax

p

 0.0001 p

 0.0002;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; (ng/mL) Turmipure > NOV > PHYT < TEP < NOV > PHYT < [Log10] STESTE STE Turmipure Turmipure Turmipure Rel. bio. p=0.0491

p

 0.0001

p

 0.0001;

p

 0.0001; between TEP < PHYT < 0 and 24 h Turmipure Turmipure [Log10]Rel. bio.

p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0001; between TEP < NOV > PHYT < 0 and 8 h Turmipure TurmipureTurmipure [Log10] Rel bio.

p

 0.0001

p

 0.0001; p

 0.0327; p

 0.0001; between TEP < NOV > PHYT < 0 and infinity Turmipure TurmipureTurmipure [Log10] Half-life

(minutes) [Log10] Terminal

elimination rate constant [Log10] Tmax

p

 0.0001

p

 0.0001; p

 0.0395;

p

 0.0001; p

 0.0001; (minutes) NOV < PHYT > NOV < PHYT < [Log10] STE STE TurmipureTurmipure

indicates data missing or illegible when filed

TABLE 58 Analysis of HHC sulfate (ng/mL) between products in the PPpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP vs NOV vs PHYTvs Turmipure Turmipure Turmipure Endpoint effect effect vs STE STE STESTE GOLD ™ GOLD ™ GOLD ™ DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; AUC0-24 h Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-24 h

p

 0.0001 p

 0.0510;

p

 0.0001; p

 0.0001; p

 0.0001;

p

 0.0001; (ng · h/mL) Turmipure > NOV > PHYT < TEP < PHYT < [Log10] STESTE STE Turmipure Turmipure DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; AUC0-8 h Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-8 h

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001;

p

 0.0001; (ng · h/mL) Turmipure > NOV > PHYT < TEP < PHYT < [Log10] STESTE STE Turmipure Turmipure DN of

p

 0.0001 p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; AUC0-infinity Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-infinity

p

 0.0001

p

 0.0322; p

 0.0001; p

 0.0186;

p

 0.0001; (ng · h/mL) NOV > PHYT < TEP < PHYT < [Log10] STE STE TurmipureTurmipure Normalized

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0252; p

 0.0001; p

 0.0001; p

 0.0001; Cmax Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng/mL/mg) STESTE STE Turmipure Turmipure Turmipure [Log10] Cmax

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; (ng/mL) Turmipure > NOV > PHYT < TEP < NOV > PHYT < [Log10] STESTE STE Turmipure Turmipure Turmipure Rel. bio.

p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0001; between TEP < NOV > PHYT < 0 and 24 h Turmipure TurmipureTurmipure [Log10] Rel. bio.

p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0001; between TEP < NOV > PHYT < 0 and 8 h Turmipure TurmipureTurmipure [Log10] Rel bio.

p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0001; between TEP < NOV > PHYT < 0 and infinity Turmipure TurmipureTurmipure [Log10] Half-life

p

 0.0001 p

 0.0011;

p

 0.0012;

p

 0.0075;

(minutes) Turmipure < NOV < TEP < [Log10] STE STE Turmipure Terminal

p

 0.0012 p

 0.0116;

p

 0.0129;

p

 0.0458;

elimination Turmipure > NOV > TEP < rate constant STE STE Turmipure[Log10] Tmax

p

 0.0001

p

 0.0001; p

 0.0001;

p

 0.0009; p

 0.0001; (minutes) NOV < PHYT > NOV < PHYT < [Log10] STE STE TurmipureTurmipure

indicates data missing or illegible when filed

TABLE 59 Analysis of curcumin and all its relative metabolites (ng/mL)between products in the PP population. Between-groupanalysis-Statistical significance of comparisons between products(adjusted p-value, Tukey adjustment) Turmipure TEP vs NOV vs PHYT vsVisit Product GOLD ™ TEP vs NOV vs PHYT vs Turmipure Turmipure TurmipureEndpoint effect effect vs STE STE STE STE GOLD ™ GOLD ™ GOLD ™ DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; AUC0-24 h Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-24 h

p

 0.0001 p

 0.0435;

p

 0.0001; p

 0.0001; p

 0.0025;

p

 0.0001; (ng · h/mL) Turmipure > NOV > PHYT < TEP < PHYT < [Log10] STESTE STE Turmipure Turmipure DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; AUC0-8 h Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-8 h

p

 0.0001 p

 0.0007;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0070; p

 0.0001; (ng · h/mL) Turmipure > NOV > PHYT < TEP < NOV > PHYT < [Log10]STE STE STE Turmipure Turmipure Turmipure DN of p = 0.0203

p

 0.0001 p

 0.0002;

p

 0.0001;

p

 0.0981;

p

 0.0034; AUC0-infinity Turmipure > NOV > TEP < PHYT < (ng · h/mL/mg) STESTE Turmipure Turmipure [Log10] AUC0-infinity

p

 0.0001

p

 ; p

 0.0481; p

 0.0001; p

 0.0011;

p

 0.0001; (ng · h/mL) TEP NOV > PHYT < TEP < PHYT < [Log10] STE STETurmipure Turmipure Normalized

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.001; p

 0.0001; Cmax Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng/mL/mg) STESTE STE Turmipure Turmipure Turmipure [Log10] Cmax

p

 0.0001 p

 0.0009;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.001; p

 0.0001; (ng/mL) Turmipure > NOV > PHYT < TEP < NOV > PHYT < [Log10] STESTE STE Turmipure Turmipure Turmipure Rel. bio.

p

 0.0001

p

 0.0001; p

 0.001; p

 0.0001; between TEP < NOV > PHYT < 0 and 24 h Turmipure TurmipureTurmipure [Log10] Rel. bio.

p

 0.0001

p

 0.0001; p

 0.001; p

 0.0001; between TEP < NOV > PHYT < 0 and 8 h Turmipure TurmipureTurmipure [Log10] Rel bio.

p

 0.0001

p

 0.0001; p

 0.001; p

 0.0001; between TEP < NOV > PHYT < 0 and infinity Turmipure TurmipureTurmipure [Log10] Half-life

p

 0.0001 p

 0.0036;

p

 0.0015;

p

 0.0112;

p

 0.0002; (minutes) Turmipure < NOV < TEP > PHYT > [Log10] STE STETurmipure Turmipure Terminal

p

 0.0001 p

 0.0037;

p

 0.0009;

p

 0.0014;

p

 0.0001; elimination Turmipure > NOV > TEP < PHYT < rate constant STESTE Turmipure Turmipure [Log10] Tmax

p

 0.0001

p

 0.0001; p

 0.0298;

p

 0.0001; p

 0.0005; (minutes) NOV < PHYT > NOV < PHYT > [Log10] STE STE TurmipureTurmipure

indicates data missing or illegible when filed

TABLE 60 Analysis of total parent compounds and their relative sulfateand glucuronide metabolites (ng/mL) between products in the PPpopulation. Between-group analysis-Statistical significance ofcomparisons between products (adjusted p-value, Tukey adjustment)Turmipure TEP vs NOV vs PHYT vs Visit Product GOLD ™ TEP vs NOV vs PHYTvs Turmipure Turmipure Turmipure Endpoint effect effect vs STE STE STESTE GOLD ™ GOLD ™ GOLD ™ DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; p

 0.0001; AUC0-24 h Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-24 h

p

 0.0001

p

 0.0001;

p

 0.0002; p

 0.0003; (ng · h/mL) PHYT < NOV > PHYT < [Log10] STE Turmipure TurmipureDN of p = 0.0310

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0002; p

 0.0001; p

 0.0001; p

 0.0001; AUC0-8 h Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-8 h

p

 0.0001

p

 0.0001; p

 0.0001;

p

 0.0001; p

 0.0001; (ng · h/mL) NOV > PHYT < NOV > PHYT < [Log10] STE STE TurmipureTurmipure DN of

p

 0.0001 p

 0.0001;

p

 0.0001; p

 0.0003; p

 0.0001; p

 0.0001; p

 0.0001; AUC0-infinity Turmipure > NOV > PHYT > TEP < NOV > PHYT < (ng ·h/mL/mg) STE STE STE Turmipure Turmipure Turmipure [Log10] AUC0-infinity

p

 0.0072

p

 0.0042;

(ng · h/mL) PHYT < [Log10] STE Normalized p = 0.0228

p

 0.0001 p

 0.0018;

p

 0.0001;

p

 0.0014; p

 0.0001;

Cmax Turmipure > NOV > TEP < NOV > (ng/mL/mg) STE STE TurmipureTurmipure [Log10] Cmax

p

 0.0001

p

 0.0001; p

 0.0020;

p

 0.0001; p

 ; (ng/mL) NOV > PHYT < NOV > PHYT < [Log10] STE STE Turmipure TurmipureRel. bio.

p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0001; between TEP < NOV > PHYT < 0 and 24 h Turmipure TurmipureTurmipure [Log10] Rel. bio.

p

 0.0001

p

 0.0001; p

 0.0001; p

 0.0001; between TEP < NOV > PHYT < 0 and 8 h Turmipure TurmipureTurmipure [Log10] Rel bio. p = 0.0362

p

 0.0213

between 0 and infinity [Log10] Half-life

p

 0.0019 p

 0.0125;

p

 0.0040;

(minutes) Turmipure < NOV < [Log10] STE STE Terminal

p

 0.0003 p

 0.0181;

p

 0.0056;

p

 0.0135; elimination Turmipure > NOV > PHYT < rate constant STE STETurmipure [Log10] Tmax

p

 0.0001

p

 0.0001; p

 0.0008;

p

 0.0001; p

 0.0047; (minutes) NOV < PHYT > NOV < PHYT > [Log10] STE STE TurmipureTurmipure

indicates data missing or illegible when filed

Serious Adverse Events:

-   -   Subject SN01-009: Cervical pain/road accident between V0 and V1        visits (under no study product) (locomotor/rheumatologic body        system, event not related to a medical history, moderate        intensity, no action on the study product, event not related to        the research and the study product, event not associated with        corrective treatments, recovery without sequelae).    -   Treatment emergent AEs with severe intensity:    -   Subject SN01-007: Lumbago between V2 and V3 visits (under        Turmipure GOLD™ product) (locomotor/rheumatologic body system,        event not related to a medical history, severe intensity, no        action on the study product, event not related to the research        and the study product, event not associated with corrective        treatments, recovery without sequelae).    -   AEs related to the study products:    -   Subject SN01-008: Headache the day of V3 visit (under Turmipure        GOLD™ product) (neurologic/psychiatric body system, event not        related to a medical history, moderate intensity, no action on        the study product, possible event related to the research and        the study product, event associated with a corrective treatment        (paracetamol), recovery without sequelae).    -   Subject SN01-030: Headache the day of V1 visit (under Turmipure        GOLD™ product) (neurologic/psychiatric body system, event not        related to a medical history, mild intensity, no action on the        study product, possible event related to the research and the        study product, event associated with a corrective treatment        (paracetamol), recovery without sequelae).    -   Subject SN01-032: Headache the day of V2 visit (under NOV        product) (neurologic/psychiatric body system, event not related        to a medical history, mild intensity, no action on the study        product, possible event related to the research and the study        product, event not associated with corrective treatments,        recovery without sequelae).

The results observed on PP population are similar to those on ITTpopulation.

Mean±SD for Total curcuminoids (ITT population) is shown below.

TABLE 61 Mean ± SD for Total curcuminoids (ITT population) STE TEP NOVPHYT Turmipure GOLD ™ product product product product productDose-normalized AUC(0-24 h) (ng · h/mL/mg) 3.7 (1.75) 3.2 (1.69) 136.1(37.40)  13.0 (9.65)  72.9 (25.49) AUC(0-24 h) (ng · h/mL/mg) 5075.6(2407.80) 4382.3 (2328.43) 8538.8 (2345.94) 2327.1 (1727.61) 6519.7(2280.33) Dose-normalized AUC(0-8 h) (ng · h/mL/mg) 1.6 (0.81) 1.2(0.52) 81.8 (19.17) 4.1 (3.83) 38.1 (12.74) AUC(0-8 h) (ng · h/mL/mg)2204.2 (1111.03) 1725.7 (723.46)  5132.6 (1202.41) 737.6 (686.44) 3410.0(1139.65) Dose-normalized AUC (0-infinity) 5.3 (5.80) 3.2 (1.68) 149.4(64.93)  14.6 (15.02) 78.3 (37.82) (ng · h/mL/mg) AUC(0-infinity) (ng ·h/mL/mg) 7273.2 (7969.82) 4370.3 (2317.23) 9369.3 (4072.30) 2618.8(2689.04) 7001.1 (3382.63) Normalized Cmax (ng/mL/mg) 0.3 (0.14) 0.3(0.10) 28.1 (7.23)  1.2 (0.80) 7.6 (3.06) Cmax (ng/mL) 444.7 (192.96)372.8 (141.70) 1762.9 (453.72)  209.1 (144.10) 678.0 (273.35) Relativebioavailability between 0 and 24 h 1.0 (0.00) 1.1 (0.79) 49.7 (37.78)4.2 (4.15) 24.2 (15.48) Relative bioavailability between 0 and 8 h 1.0(0.00) 1.1 (1.07) 72.2 (58.68) 2.9 (2.50) 30.6 (20.00) Relativebioavailability between 0 and infinity 1.0 (0.00) 1.0 (0.75) 49.3(37.74) 3.7 (4.13) 22.9 (15.28) Half-life (minutes)  788.4 (1233.91)505.2 (265.35) 337.3 (278.83) 640.1 (399.12) 318.3 (154.44) Terminalelimination rate constant 0.1 (0.05) 0.1 (0.04) 0.2 (0.05) 0.1 (0.05)0.2 (0.06) Time to peak (minutes) 256.5 (181.69) 330.3 (341.21) 61.0(18.45) 375.0 (249.39) 189.5 (147.52)

CONCLUSION

The results demonstrate that there are few differences between thebioavailability of the compounds found in TEP and STE (only 5differences).

The composition within the scope of the present invention (TurmipureGOLD™) was found to provide better bioavailability of compounds thanSTE, TEP and PHYT, and was able to provide a similar bioavailability toNOV despite being administered at a lower dose (300 mg compared to 1000mg) and using only natural ingredients with no synthetic carriers (suchas polysorbate 80).

More specifically, Novasol was used at 1000 mg whereas the compositionof the present invention (Turmipure GOLD™) was at 300 mg. As Turmipureyields an effect of 6520 (AUC in ng·h/mL) at 300 mg, if it were used atthe same dosage as Novasol (1000 mg), it would yield an effect of 21733(AUC in ng·h/mL), which is much higher than the effect of Novasol at thesame dosage (8539).

1. A composition comprising: (i) at least about 20% curcuminoids byweight of the composition; (ii) gum arabic; and (iii) an extractobtained or obtainable from quillaja, wherein the composition comprisesparticles having an average diameter of from about 100 nm to about 10000nm.
 2. A composition according to claim 1, wherein the particles have anaverage diameter of from about 100 nm to about 700 nm
 3. A compositionaccording to claim 1 or 2 further comprising plant and/or vegetable oil.4. A composition according to any one of claims 1 to 3, wherein thequillaja extract is present in an amount from about 0.1 to about 5% byweight of the composition.
 5. A composition according to any one of thepreceding claims, wherein the gum arabic is present in an amount fromabout 40 to about 60% by weight of the composition.
 6. A compositionaccording to any one of the preceding claims, wherein the quillajaextract comprises at least 50% saponins.
 7. A composition according toany one of the preceding claims, wherein the quillaja extract is in theform of a solid.
 8. The use of a composition according to any one ofclaims 1 to 7 as nutraceutical formulation, a dietary or food productfor humans or animals (such as functional food formulations, i.e. food,drink, feed or pet food or a food, drink, feed or pet food supplements),a nutritional supplement, a fragrance or flavouring, a pharmaceutical orveterinary formulation, an oenological or cosmetic formulation.
 9. Theuse of a composition according to any one of claims 1 to 7 in thepreparation of a nutraceutical formulation, a dietary or food productfor humans or animals (such as functional food formulations, i.e. food,drink, feed or pet food or a food, drink, feed or pet food supplements),a nutritional supplement, a fragrance or flavouring, a pharmaceutical orveterinary formulation, an oenological or cosmetic formulation.
 10. Anutraceutical formulation, a dietary or food product for humans oranimals (such as functional food formulations, i.e. food, drink, feed orpet food or a food, drink, feed or pet food supplements), a nutritionalsupplement, a fragrance or flavouring, a pharmaceutical or veterinaryformulation, an oenological or cosmetic formulation consisting of,consisting essentially of or comprising a composition as defined in anyone of claims 1 to
 7. 11. The use according to claims 8 or 9, whereinthe nutraceutical formulation, dietary or food product for humans oranimals (such as functional food formulations, i.e. food, drink, feed orpet food or a food, drink, feed or pet food supplements), nutritionalsupplement, fragrance or flavouring, pharmaceutical or veterinaryformulation, oenological formulation or cosmetic formulation furthercomprises pharmaceutically/veterinary ingredients, such as excipients orcarriers or (function) food acceptable ingredients and mixtures thereofas appropriate.
 12. The nutraceutical formulation, dietary or foodproduct for humans or animals (such as functional food formulations,i.e. food, drink, feed or pet food or a food, drink, feed or pet foodsupplements), nutritional supplement, fragrance or flavouring,pharmaceutical or veterinary formulation, oenological formulation orcosmetic formulation according to claim 9, further comprisingpharmaceutically/veterinary ingredients, such as excipients or carriersor (function) food acceptable ingredients and mixtures thereof asappropriate.
 13. A process for the preparation of a composition asdefined in claims 1 to 7, wherein the process comprises the steps of:(i) preparing an aqueous solution of curcuminoids; (ii) mixing theaqueous solution from (i) with an aqueous gum arabic solution andextract obtained or obtainable from quillaja and optionally a plantand/or vegetable oil to provide an emulsion; and optionally (iii) dryingthe product of (ii) to provide a composition comprises particles havingan average diameter of from about 100 nm to about 10000 nm.